Modulation of pathogenicity

ABSTRACT

The present invention relates to the use of compounds of the general Formula (I): 
     
       
         
         
             
             
         
       
     
     wherein in Formula (I),
         R is H, alkyl, cycloalkyl, aryl or heteroaryl;   R 1  is H, alkyl, cycloalkyl, aryl or heteroaryl;   R 2  is H, alkyl, cycloalkyl, aryl or heteroaryl;   A 1  and A 2  each independently represent an optionally substituted C 1 -C 20 -alkyl group which may contain one or more group(s) Z, or a monocyclic or polycyclic optionally substituted aromatic or non-aromatic ring system which may contain one or more group(s) X, and in case of a polycyclic ring system, said system contains at least one aromatic ring;   Z is selected from the group consisting of S, O, N, NR 4 , CO, CO 2 , CS, SO or SO 2      X is selected from the group consisting of S, O, N, NR 4 , SO or SO 2 ;

STATEMENT OF RELATED APPLICATIONS

The present application is a divisional of co-pending application Ser.No. 10/429,875, filed May 6, 2003, which is a continuation-in-part ofapplication Ser. No. 10/094,301, filed Mar. 8, 2002, now abandoned, thecontents of each are herein incorporated by reference in their entirety.

BACKGROUND OF THE INVENTION

The present invention relates to the use of compounds such as amide,carbazide and hydrazide derivatives as selective inhibitors of bacterialpathogens. In particular the invention refers to a family of compoundsthat block the quorum sensing system of Gram-negative bacteria, aprocess for their manufacture, pharmaceutical compositions containingthem and to their use for the treatment and prevention of microbialdamages and diseases, in particular for diseases where there is anadvantage in inhibiting quorum sensing regulated phenotypes ofpathogens.

Many microorganisms, including bacteria, fungi, protozoa and algae causesevere damages or diseases in different areas such as industry,agriculture, environment and medicine. Especially bacteria as humanpathogens cause tremendous costs in public health systems worldwide. Thecontinuing emergence of multiple-drug-resistant bacterial strains hasnecessitated finding new compounds that can be used in antibacterialtreatment. There are two broad strategies for the control of bacterialinfection: either to kill the organism or to attenuate its virulencesuch that it fails to adapt to the host environment. The latter approachhas, however, lacked specific targets for rational drug design. Thediscovery that Gram-negative bacteria employ a signal transductionpathway comprising a small molecule to globally regulate the productionof virulence determinants offers such a novel target.

A wide variety of Gram-negative bacteria produce N-acyl-L-homoserinelactone (AHL or HSL, FIG. 1) derivatives as signal molecules inintercellular communication. These molecules, also referred to as“pheromones” or “quoromones”, comprise a homoserine lactone moietylinked to an acyl side chain. Bacteria use this signaling system tomonitor their population cell density in a process referred to as“quorum sensing”. In each cell of a population an HSL synthase fromusually the LuxI family of proteins produce a low basal level ofdiffusible HSLs. The HSL concentration increases with bacterialpopulation density until a threshold concentration is reached whichresults in expression of various HSL-dependent genes through anHSL-receptor protein belonging generally to the LuxR family oftranscriptional regulators. This HSL-receptor protein complex serves notonly as positive transcription regulator of quorum sensing regulatedgenes but also as positive regulator for the HSL synthesis itself.Therefore, the entire system is amplified via a process ofautoinduction.

This system was first discovered in the bioluminescent marine bacteriaVibrio harveyi and V. fischeri where it is used to controlbioluminescence expression. In recent years it has become apparent thatmany Gram-negative bacteria employ one or more quorum sensing systemscomprising HSL derivatives with different acyl side chains to regulatein a cell-density dependent manner a wide variety of physiologicalprocesses such as swarming motility, biofilm formation, pathogenicity,conjugation, bioluminescence or production of pigments and antibiotics(Table 1, for reviews and further references see, e.g.: Fuqua et al,Ann. Rev. Microbiol. 50:727-51, 1996; Fuqua & Greenberg, Curr. OpinionMicrobiol. 1:183-89, 1998; Eberl, Syst. Appl. Microbiol. 22:493-506,1999; De Kievit & Iglewski, Infect. Immun. 68:4839-49, 2000).

TABLE 1 Summary of HSL-based quorum sensing systems Regulatory Bacteriumproteins Major HSL HSL-regulated phenotype Aeromonas hydrophila AhyR,AhyI C4-HSL Extracellular protease, biofilm formation Aeromonassalmonicida AsaR, AsaI C4-HSL Extracellular protease Agrobacteriumtumefaciens TraR, TraI 3-oxo-C8-HSL Conjugal transfer Burkholderiacepacia CepR, CepI C8-HSL Protease, lipase, ornibactin synthesis,biofilm formation, swarming motility Chromobacterium violaceum CviR,CviI C6-HSL Antibiotics, violacein, exoenzymes, cyanide Enterobacteragglomerans EagR, EagI 3-oxo-C6-HSL Unknown Erwinia carotovora CarR,(CarI) 3-oxo-C6-HSL Carbapenem antibiotics, ExpR, ExpI exoenzymeproduction Erwinia chrysanthemi ExpR, ExpI 3-oxo-C6-HSL Pectinaseexpression (EchR, EchI) Escherichia coli SdiA Unknown Cell division,virulence factor production Nitrosomonas europaea Unknown 3-oxo-C6-HSLEmergence from lag phase Obesumbacterium proteus OprR, OprI 3-oxo-C6-HSLUnknown Pantoea stewartii EsaR, EsaI 3-oxo-C6-HSL Exopolysaccharideproduction, virulence factor production Pseudomonas aeruginosa LasR,LasI 3-oxo-C12- Extracellular virulence HSL factors, Xcp, biofilmformation, RpoS, RhlR Pseudomonas aeruginosa RhlR, RhlI C4-HSLExtracellular virulence factors, cyanide, lectins, pyocyanin,rhamnolipid, type 4 pili, twitching motility Pseudomonas aureofaciensPhzR, PhzI C6-HSL Phenazine antibiotics Pseudomonas fluorescens HdtS3-hydroxy-7- Unknown cis-C14-HSL Ralstonia solanacearum SolR, SolIC8-HSL Unknown Rhizobium etli RaiR, RaiI 7 HSLs Root nodulationRhizobium leguminosarum RhiR 3-hydroxy-7- Nodulation, bacteriocin,cis-C14-HSL stationary phase survival Rhizobium leguminosarum RhiR, RhiIC6-HSL, rhizome interactions C8-HSL Rhodobacter sphaeroides CerR, CerI7-cis-CH-HSL Clumping factor Serratia liquefaciens SwrR, SwrI C4-HSLSwarming motility, protease, serrawettin W2, lipase Vibrio anguillarumVanR, VanI 3-oxo-C10- Unknown HSL Vibrio anguillarum VanM, VanN C6-HSL,Unknown 3-hydroxy-C6- HSL Vibrio fischeri LuxR, LuxI 3-oxo-C6-HSLBioluminescence Vibrio harveyi LuxM, LuxN 3-hydroxy-C4- Bioluminescence,PHB HSL synthesis Xenorhabdus nematophilus Unknown 3-hydroxy-C4-Virulence HSL Yersinia enterocolitica YenR, YenI C6-HSL, Unknown3-oxo-C6-HSL Yersinia pestis YpeR, YpeI Unknown Unknown Yersiniapseudotuberculosis YpsR, YpsI 3-oxo-C6-HSL Motility, clumping Yersiniapseudotuberculosis YtbR, YtbI C8-HSL Unknown Yersinia ruckeri YukR, YukIUnknown Unknown

With regard to bacteria that utilize HSL-based quorum sensing as part oftheir lifestyle, Pseudomonas aeruginosa is perhaps the best understoodin terms of the role quorum sensing plays in pathogenicity. In thishuman opportunistic pathogen, which causes nosocomial infections inimmunocompromised patients and has an extremely high potential todevelop resistance mechanisms against traditional antibiotic treatment,production of many virulence factors including expression of alkalineprotease, endoproteinase, LasA protease, LasB elastase, anthranilatesynthase, hemolysins, lectin, cytochrome c oxidase, catalase, Mn- andFe-dependent superoxide dismutases, exotoxin A, exoenzyme S, chitinase,chitin binding protein, phenazine, hydrogen cyanide, pyocyanin,pyoverdine, phospholipase C, rhamnolipids, sigma factor S, components ofthe protein secretion apparatus, efflux transporters, production ofalginate and adhesion, twitching motility and pilin export is regulatedby two interlinked quorum sensing circuits, Moreover, it has beendemonstrated that this signaling system is involved in the ability of P.aeruginosa to form biofilms (Davies et al, Science 280:295-8, 1998).Recently Huber et al. (Microbiology 147:2517-28, 2001) demonstrated thatbiofilm formation and swarming motility of Burkholderia cepacia, like P.aeruginosa a human opportunistic pathogen, is also dependent on anHSL-based quorum sensing system.

Biofilms are defined as an association of microorganisms growingattached to a surface and producing a slime layer of extracellularpolymers in which the microbial consortia is embedded in a protectiveenvironment (for a review see: Costerton et al., Ann. Rev. Microbiol.49:711-45, 1995). Biofilms represent a severe problem as bacteriaintegrated in such a polymer matrix develop resistance to conventionalantimicrobial agents. P. aeruginosa cells, for example, growing in analginate slime matrix have been demonstrated to be resistant toantibiotics (e.g., aminoglycosides, β-lactam antibiotics,fluoroquinolones) and disinfectants (Govan & Deretic, Microbiol. Rev.60:539-74, 1996). Several mechanisms for biofilm-mediated resistancedevelopment have been proposed (Costerton et al., Science 284:1318-22,1999).

In most natural, clinical and industrial settings bacteria arepredominantly found in biofilms. Drinking water pipes, ship hulls, teethor medical devices represent typical surfaces colonized by bacteria. Onthe one hand biofilms decrease the life time of materials throughcorrosive action in the industrial field, a process also referred to as“biofouling”. Furthermore, microbial biofilms growing for example onship hulls increase fuel consumption through enhanced frictionalresistance and simultaneously reduce maneuverability. On the other handtwo thirds of all bacterial infections in humans are associated withbiofilms (Lewis, Antimicrob. Agents Chemother. 45:999-1007, 2001).

Pseudomonas aeruginosa, for example, forms infectious biofilms onsurfaces as diverse as cystic fibrosis lung tissue, contact lenses, andCatheter tubes (Stickler et al., Appl. Environm. Microbiol. 64:3486-90,1998). Burkholderia cepacia also forms biofilms in lungs of cysticfibrosis patients and is a major industrial contaminant (Govan et al.,J. Med. Microbiol. 45:395-407, 1996). Since biofilm formation of bothorganisms is demonstrated to require an HSL signaling system, inhibitionof their quorum sensing systems would result in an impaired ability toform biofilms and therefore in an increased susceptability toantibacterial treatment.

Beside the role of HSL derivatives as signaling molecules of bacterialcell-to-cell communication it has been demonstrated that HSL interferealso with higher organisms. Since HSL derivatives inhibit murine andhuman leucocyte proliferation and TNF-alpha secretion bylipopolysaccharide (LPS) stimulated human leucocytes (Chhabra et al., J.Med. Chem. 46:97-104, 2003), the suitability of these compounds forimmunological diseases, particularly autoimmune diseases such aspsoriasis, rheumatoid arthritis, multiple sclerosis and type 1(autoimmune) diabetes is indicated (WO 03/004017, WO 03/022828).

Furthermore, certain HSL molecules are capable of reducing the heartbeat without substancially reducing arterial blood pressure. Thesecompounds and analogs of them could, therefore, be suitable for thetreatment of cardiac tachyarrhythmias, ischaemic heart disease,congestive heart failure (WO 01/26650). Additionally, HSL compounds havebeen reported as possible antiallergic drug (WO 95/01175) and for thetreatment of a range of diseases including cancer, breast cancer,obesity, lipid metabolism disorders, immune disease, immune deficiencyor immune disorders by modulating STAT activity (WO 03/026641).

The discovery that a wide spectrum of bacterial organisms use quorumsensing to control virulence factor production and other phenotypes suchas biofilm formation makes it an attractive target for antimicrobialtherapy. Pathogenic organisms using this signaling system to controlvirulence could potentially be rendered avirulent by blocking thiscell-cell communication system. In contrast to traditional antibiotics,the risk of resistance development seems to be very low, since quorumsensing blocking agents would not kill the organism but disturb signaltransduction pathways. There are several possibilities of interruptingthe quorum sensing circuit.

For example, plants expressing an HSL-lactonase enzyme originallyderived from Bacillus sp. have been demonstrated to quench pathogenquorum sensing signaling and to significantly enhance resistance toErwinia carotovora infections (Dong et al., Nature 411:813-7, 2001). Analternative way to block cell signaling could be to interrupt the HSLsynthesis by using analogs of HSL precursors.

However, the most promising possibility to block quorum sensing is totake advantage of the unique specificity the HSLs and HSL-receptorproteins show for one another. The ability of homoserine lactone-basedanalogs to inhibit activation of HSL-receptor proteins has already beendemonstrated in a number of bacteria including Vibrio fischeri (Schaeferet al, J. Bacteriol. 178:2897-901, 1996), Agrobacterium tumefaciens (Zhuet al., J. Bacteriol. 180:5398-405, 1998), Chromobacterium violaceum(McLean et al., Microbiology 143:3703-11, 1997), Aeromonas salmonicida(Swift et al., J. Bacteriol. 179:5271-81, 1997) and Pseudomonasaeruginosa (Pesci et al., J. Bacteriol. 179:3127-32, 1997). However,none of these compounds have been developed as antimicrobial agents,e.g. in medical therapy, so far.

The are only few non-HSL-based antimicrobials described which aresupposed to interfere specifically with HSL-regulated processes, forexample halogenated furanone derivatives which are structurally similarto HSLs and have been isolated from red marine algae Delisea pulchra (WO96129392; Hentzer et al., Microbiology 148:87-102, 2002). Additionally,these substances have been demonstrated to inhibit also Gram-positivebacteria (WO 99/53915). However, the use of most of these furanonecompounds is limited due to their toxicity making them unsuitable forveterinary and medical applications.

Furthermore, Smith et al. (Chem. Biol., 10:81-9, 2003) recentlypublished Pseudomonas aeruginosa HSL analogs with slight structuralvariations targeted to the HSL moiety which act both as quorum sensingagonists and antagonists. Additionally, WO 02/088298 reportedly providescertain nitrogen heterocyclic molecules for controlling biofilms basedon the interference with quorum sensing.

Many target genes involved in biofilm formation, methods of screeningfor compounds to control biofilm development and HSL-based compositionsto prevent biofilm formation have been described (WO 99/55368, WO98/57618, WO 99/27786, WO 98/58075), but until now no promisingantibacterial drug candidate has been developed that is capable ofinhibiting virulence gene expression and biofilm formation in differentareas, preferentially in the medical field.

It is an object of the present invention to provide compounds blockingspecifically quorum sensing regulated processes without inhibitingbacterial growth, Furthermore, these compounds should not be structuralderivatives of the homoserine lactone family of regulatory compounds andshould not exhibit any toxic properties.

BRIEF SUMMARY OF THE INVENTION

Accordingly, we have been able to find compounds that can significantlyreduce virulence gene expression and biofilm formation of several humanpathogens. In contrast to the furanones the compounds of this inventiondo not show any toxic effect and are therefore suitable for applicationsin a wide area. Such applications could be the use of the compounds forinstance as new antibiotic therapeutics, disinfectants, antifoulingcoatings or coatings of medical devices. In contrast to traditionalantibacterial agents (like amide or 1,2-acylhydrazine derivatives in WO01/51456; for the synthesis of amide or 1,2-acylhydrazine derivativessee also EP 638545 and EP 982292), the compounds of the presentinvention do not kill the microorganisms, but render them avirulent. Theadvantage of this alternative strategy is that the emergence ofbacterial resistance against such antimicrobials is extremelyimprobable.

In general, the present invention provides compounds selectivelymodulating bacterial cell-cell communication. Through inhibition of thiscommunication system the expression of many HSL-dependent virulencegenes and other phenotypes like swarming motility and biofilm formationare significantly reduced or completely abolished rendering a bacterialpopulation more susceptible to the host immune-response or to treatmentwith traditional antibacterial agents.

Thus, in one aspect, the invention refers to a method for inhibiting anHSL-regulated process in a microorganism by exposing the microorganismto a new class of compounds with an inhibitory effect on bacterialsignaling.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a general N-acyl-L-homoserine lactone structure wherethe depicted R is an acyl side chain;

FIG. 2 graphically illustrates the influence of representative compoundsof the present invention on the growth of E. coli MT102 (pSB403);

FIG. 3 graphically illustrates the inhibitory effect of representativecompounds of the present invention on the protease production of P.aeruginosa PAO-JP2;

FIG. 4 graphically illustrates the influence of representative compoundsof the present invention on the growth of P. aeruginosa PAO-JP2;

FIG. 5A graphically illustrates the inhibitory effect of representativecompounds of the present invention (0.4 mM) on biofilm formation ofBurkholderia cepacia H111, with statistical data of at least five (5)separate representative experiments;

FIG. 5B is an illustration of a microtitre dish;

FIG. 6 graphically illustrates the influence of representative compoundsof the present invention (0.4 mM) on the growth of Burkholderia cepaciaH111.

DETAILED DESCRIPTION OF THE INVENTION

The present invention therefore refers to compounds of the generalFormula (I)

wherein

-   R is H, alkyl, cycloalkyl, aryl or heteroaryl;-   R¹ is H, alkyl, cycloalkyl, aryl or heteroaryl;-   R² is H, alkyl, cycloalkyl, aryl or heteroaryl;-   A¹ and A² each independently represent an optionally substituted    C₁-C₂₀-alkyl group which may contain one or more group(s) Z, or a    monocyclic or polycyclic optionally substituted aromatic or    non-aromatic rind system which may contain one or more group(s) X,    and in case of a polycyclic ring system, said system contains at    least one aromatic ring;-   Z is selected from the group consisting of S, O, N, NR⁴, CO, CO₂,    CS, SO or SO₂-   X is selected from the group consisting of S, O, N, NR⁴, SO or SO₂;-   said substituted ring system carries a substituent R³ on one or more    of the carbon atoms of said ring system;-   said substituted C₁-C₂₀-alkyl group carries a substituent R³ on one    or more of the carbon atoms of said alkyl group;-   R³ is independently H, OR⁴, SR⁴, hydroxyalkyl, hydroxyalkylamino,    cycloalkyl, halogen, haloalkyl, haloalkyloxy, NO₂, CN, SO₂NR⁴R⁵,    CO₂NR⁴R⁵, COR⁴, CO₂R⁴, SO₂R⁴, SO₃R⁴, NR⁴R⁵, alkyl, aryl or    heteroaryl;-   R^(3′) is independently H, OR⁴, SR⁴, hydroxyalkyl,    hydroxyalkylamino, cycloalkyl, halogen, haloalkyl, haloalkyloxy,    NO₂, CN, SO₂NR⁴R⁵, CO₂R⁴R⁵, COR⁴, CO₂R⁴, SO₂R⁴, SO₃R⁴, NR⁴R⁵, alkyl,    aryl or heteroaryl;-   R^(3″) is independently H, OR⁴, SR⁴, hydroxyalkyl,    hydroxyalkylamino, cycloalkyl, halogen, haloalkyl, haloalkyloxy,    NO₂, CN, SO₂NR⁴R⁵, CO₂NR⁴R⁵, COR⁴, CO₂R⁴, SO₂R⁴, SO₃R⁴, NR⁴R⁵,    alkyl, aryl or heteroaryl;-   R⁴ is H, alkyl, cycloalkyl, aryl or heteroaryl;-   R⁵ is H, O-alkyl, O-aryl, alkyl, heteroaryl or aryl;-   Y¹ and Y² are independent from each other C═O, C═S, SO₂, or C═NR⁵;-   p is 0, n is 0;-   or p is 0, n is 1;-   or p is 1, n is 0;-   or p is 1, n is 1;

In Formula (I) the following definitions are used:

-   an alkyl group, if not stated otherwise, denotes a linear or    branched C₁-C₆-alkyl, preferably a linear or branched chain of one    to five carbon atoms, a linear or branched C₁-C₆-alkenyl or a linear    or branched C₁-C₆-alkinyl group, which can optionally be substituted    by one or more substituents R³, preferably by halogen;-   the C₁-C₆-alkyl, C₁-C₆-alkenyl and C₁-C₆-alkinyl residue may be    selected from the group comprising —CH₃, —C₂H₅, —CH═CH₂, —C≡CH,    —C₃H₇, —CH(CH)₂, —CH₂—CH═CH₂, —C(CH₃)═CH₂, —CH═CH—CH₃, —C≡C—CH₃,    —CH₂═C≡CH, —C₄H₉, —CH₂—CH(CH₃)₂, —CH(CH₃)—C₂H₅, —C(CH₃)₃, —C₅H₁₁,    —C₆H₁₃, —C(R₃)³, —CR³(R^(3′))₂, —CR³(R^(3′))R^(3″), —C₂(R³)₅,    —CH₂—C(R³)₃, —CH₂—CR³(R^(3′))₂, —CH₂—CR³(R^(3′))R^(3″), —C₃(R³)₇,    —C₃(R³)₇, —C₂H₄—C(R³)₃, —C₂H₄—CH═CH₂, —CH═CH—C₂H₅, —CH═C(CH₃)₂,    —CH₂—CH═CH—CH₃, —CH═CH—CH═CH₂, —C₂H₄—C≡CH, —C≡C—C₂H₅, —CH₂—C≡CH₃,    —C≡C—CH═CH₂, —CH═CH—C≡CH, —C≡C—C≡CH, —C₂H₄—CH(CH₃)₂, —CH(CH₃)—C₃H₇,    —CH₂—(CH₃)—C₂H₅, —CH(CH₃)—CH(CH₃)₂, —C(CH₃)₂—CH₅, —CH₂—C(CH₃)₃,    —C₃H₆—CH═CH₂, —CH═CH—C₃H₇, —C₂H₄—CH═CH—CH₃, —CH₂—CH═CH—C₂H₅,    —CH₂—CH═CH—CH═CH₂, —CH═CH—CH═CH—CH₃, —CH═C—CH₂—CH═CH₂,    —C(CH₃)═CH—CH═CH₂, —CH═C(CH₃)—CH═CH₂, —CH═CH—C(CH₃)═CH₂,    —CH₂—CH═C(CH₃)₂, —C(CH₃)═C(CH₃)₂, —C₃H₆—C≡CH, —C≡C—C₃H₇,    —C₂H₄—C≡CH₃, —CH—C≡C—C₂H₅, —CH₂—C≡C—CH₂, —CH₂—CH═CH—C≡CH,    —CH₂—C≡C—C≡CH, —C≡C—CH═CH—CH₃, —CH═CH—C≡C—CH₃, —C≡C—C≡C—CH₃,    —C≡C—CH₂—CH═CH₂, —CH═CH—CH₂—C≡CH, —C≡C—CH₂—C≡CH,    —C(CH₃)═CH—CH—CH═CH₂, —CH═CH₃)—CH═CH₂, —CH═CH—C(CH₃)═CH₂,    —C(CH₃)═CH—C≡CH, —CH═C(CH₃)—C≡CH, —C≡C—C(CH₃)═CH₂, —C₃H₆—CH(CH₃)₂,    —C₂H₄—(CH₃)—C₂H₅, —CH(CH₃)—C₄H₉, —CH₂—CH(CH₃)—C₃H₇,    —CH(CH₃)—CH₂—CH(CH₃)₂, —CH(CH₃)—CH(CH₃)—C₂H₅, —CH₂—CH(CH₃)—CH(CH₃)₂,    —CH₂—C(CH₃)₂—C₂H₅, —C(CH₃)₂—C₃H₇, —C(CH₃)₂—CH(CH₃)₂, —C₂H₄—C(CH₃)₃,    —CH(CH₃)—C(CH₃)₃, —C₄H₈H═CH₂, —CH═CH—C₄H₉, —C₃H₆—CH═CH—CH₃,    —CH₂—H═CH—C₃H₇, —C₂H₄—CH═CH—C₂H₅, —CH₂—C(CH₃)═C(CH₃)₂,    —C₂H₄—CH═C(CH₃)₂, —C₄H₈—C≡CH, —C≡C—C₄H₉, —C₃H₆—C≡C—CH₃,    —CH₂—C≡C—C₃H₇, —C₂H₄—C≡C—C₂H₅;-   a cycloalkyl group denotes a non-aromatic ring system containing    three to eight carbon atoms, preferably four to eight carbon atoms,    wherein one or more of the carbon atoms in the ring can be    substituted by a group X, X being as defined above; the    C₃-C₈-cycloalkyl residue may be selected from the group comprising    -cyclo-C₃H₅, -cyclo-C₄H₇, -cyclo-C₅H₉, -cyclo-C₆H₁₁, -cyclo-C₇H₁₃,    -cyclo-C₈H₁₅;-   an alkoxy group denotes an O-alkyl group, the alkyl group being as    defined above; the alkoxy group is preferably a methoxy, ethoxy,    isopropoxy, t-butoxy or pentoxy group;-   an haloalkyl group denotes an alkyl group which is substituted by    one to five halogen atoms, the alkyl group being as defined above;    the haloalkyl group is preferably a —C(R¹⁰)₃, —CR¹⁰(R^(10′))₂,    —CR¹⁰(R^(10′))R^(10″), —C₂(R¹⁰)₅, —CH₂—C(R¹⁰)₃, —CH₂—CR¹⁰(R^(10′))₂,    —CH₂—CR¹⁰(R^(10′))R^(10″), —C₃(R¹⁰)₇ or —C₂H₄—C(R¹⁰)₃, wherein R¹⁰,    R^(10′), R^(10″) represent F, Cl, Br or I, preferably F;-   a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group    being as defined above;-   an haloalkyloxy group denotes an alkoxy group which is substituted    by one to five halogen atoms, the alkyl group being as defined    above; the haloalkyloxy group is preferably a —OC(R¹⁰)₃,    —OCR¹⁰(R^(10′))₂, —OCR¹⁰(R^(10′))R^(10″), —OC₂(R^(10″))₅,    —OCH₂—(R¹⁰)₃, —OCH₂—CR¹⁰(R^(10′))₂, —OCH₂—CR¹⁰(R^(10′))R^(10″),    —OC₃(R¹⁰)₇ or —OC₂H₄—C(R¹⁰)₃, wherein R¹⁰, R^(10′), R^(10″),    represent F, Cl, Br or I, preferably F;-   a hydroxyalkylamino group denotes an (HO-alkyl)₂-N-group or    HO-alkyl-NH-group, the alkyl group being as defined above;-   a halogen group is chlorine, bromine, fluorine or iodine;-   an aryl group preferably denotes an aromatic group having five to    fifteen carbon atoms, which can optionally be substituted by one or    more substituents R³, where R³ is as defined above; the aryl group    is preferably a phenyl group, —CH₂—C₆H₄, —C₂H₄—C₆H₄, —CH═CH—C₆H₄,    —C≡C—C₆H₄, -o-C₆H₄—R³, -m-C₆₄—R³, -p-C₆H₄R³, -o-CH₂—C₆H₄—R³,    -m-CH₂—C₆H₄—R³, -p-CH₂—C₆H₄—R³;-   a heteroaryl group denotes a 5- or 6-membered heterocyclic group    which contains at least one heteroatom like O, N, S. This    heterocyclic group can be fused to another ring. For example, this    group can be selected from an oxazol-2-yl, oxazol-4-yl, oxazol-5-yl,    thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl,    isothiazol-4-yl, isothiazol-5-yl, 1,2,4-oxadiazol-3-yl,    1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl,    1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl, 1,2,5-thiadiazol-3-yl,    1-imidazolyl, 2-imidazolyl, 1,2,5-thiadiazol-4-yl, 4-imidazolyl,    1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl,    3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl,    4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl,    2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, indolyl,    indolinyl, benzo-[b]-furanyl, benzo[b]thiophenyl, benzimidazolyl,    benzothiazolyl, quinazolinyl, quinoxazolinyl, or preferably    isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, quinolinyl,    tetrahydro-quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl group.    This heterocyclic group can optionally be substituted by one or more    substituents R³, where R³ is as defined above.

In Formula (I), A¹ or A² each independently represent a C₁-C₂₀-alkylgroup which is optionally substituted by one or more substituents R³, ora monocyclic or polycyclic aromatic or non-aromatic ring system which isoptionally substituted by one or more substituents R³ and in case of anaromatic ring system contains at least one aromatic ring. The optionallysubstituted monocyclic or polycyclic aromatic or non-aromatic ringsystem may also contain one or more groups X selected from S, O, N, NR⁴,SO or SO₂. In preferred embodiments, A¹ and A² each independentlyrepresent an optionally substituted C₁-C₂₀-alkyl group or an optionallysubstituted monocyclic or bicyclic aromatic ring system. In case ofsubstitutions of carbon atoms in the ring system, preferably one, two orthree carbon atoms am substituted by a group X, wherein X is selectedfrom the group consisting of S, O, N, NR⁴, SO or SO₂. In one preferredembodiment, one of the carbon atoms is substituted by a group X═O, S,NH.

In Formula (I), A¹ and/or A² independently represent an optionallysubstituted C₁-C₂₀-alkyl group which is optionally substituted by one ormore substituents R³. Preferably A¹ and/or A² independently represent anoptionally substituted C₁-C₁₂-alkyl group, said alkyl group may be astraight chain or branched chain alkyl group, and examples includemethyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl,hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl groups. The termalkyl group also contains alkenyl and alkinyl groups, that means thatthe alkyl group contains one or more double or triple bounds.

In Formula (I), A¹ and/or A² represent an optionally aromatic ornon-aromatic ring system, which is substituted by one or moresubstituents R³, said ring system may be a phenyl, 1-naphthyl,2-napthyl, 1-anthracenyl, 2-anthracenyl, 2-pyranyl, 3-pyranyl,4-pyranyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyland 5-oxazolyl, in particular 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl,2-pyrazinyl, 3-pyrazinyl, 1-imidazolyl, 2-imidazolyl, 2-thienyl,3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,benzothiophene, pyrazolo[3,4-b]-pyridyl, 2-pyrimidyl, 4-pyrimidyl and9H-thioxanthene-10,10-dioxide ring, in which the ring system can befused to one or more other monocyclic aromatic or non-aromatic rings.

Suitable substituents for A¹ and/or A² are independently H, CO₂R⁴, COR⁴,CONR⁴R⁵, NR⁴R⁵, OR⁴, SR⁴, hydroxyalkylamino, NO₂, CN, hydroxylalkyl,halogen, haloalkyl, haloalkyloxy, SO₂NR⁴R⁵, CO₂NR⁴R⁵, CO₂R⁴, SO₂R⁴,SO₃R⁴, NR⁴R⁵, alkyl, cycloalkyl, arylalkyl, aryl or heteroaryl.

Furthermore the present invention is directed to novel compounds of thegeneral Formula (X) and pharmaceutically acceptable salts thereof:

wherein

-   A³ is an optionally substituted C₃-C₂₀-alkyl group or

-   an C₃-C₂₀-alkyl group denotes a linear or branched C₃-C₂₀-alkyl    group, which is optionally substituted by R³, R³ being as defined    below; the C₃-C₂₀-alkyl residue may be selected from the group    comprising —C₃H₇, —CH(CH₃)₂, —CH₄H₉, —CH₂—CH(CH₃)₂, —CH(CH₃)—C₂H₅,    —CH₂—CH(CH₃)—CH₃, —C(CH₃)₃, —C₅H_(C3)H₇, —CH₂—CH(CH₃)—C₂H₅,    —CH(CH₃)—CH(CH₃)₂, —C(CH₃)₂—C₂H₅, —CH₂—C(CH₃)₃, —C₆H₁₃,    —C₃H₆—CH(CH₃)₂, —C₂H₄—CH(CH₃)—C₂H₅, —CH(CH₃)—C₄H₉,    —CH₂—CH(CH₃)—C₃H₇, —CH(CH₃)—CH₂—CH(CH₃)₂, —CH(CH₃)—CH(CH₃)—C₂H₅,    —CH₂—CH(CH₃)—CH(CH₃)₂), —CH₂—C(CH₃)₂—C₂H₅, —C(CH₃)₂—C₃H₇,    —C(CH₃)₂CH(CH₃)₂, —C₂H₄—C(CH₃)₃, —CH(CH₃)—C(CH₃)₃, —C₇H₁₅,    —C₃H₆—C(CH₃)₃, —C₄H₈—CH(CH₃)₂, —C₃H₆—CH(CH₃)—C₂H₅,    —C₂H₄—C(CH₃)₂—C₃H₅, —C₂H₄—CH(CH₃)—C₃H₇, —CH₂—C(CH₃)₂—C₃H₇,    —CH₂—CH(CH₃)—C₄H₉, —CH(CH₃)—C₅H₁₁, —C(CH₃)₂—CH₃,    —C(CH₃)₂—CH₂—CH(CH₃)₂, —CH(CH₃)—C₂H₄—CH(CH₃)₂,    —CH₂—CH(CH₃)—CH₂—CH(CH₃)₂, —CH₂—C(CH₃)₂—CH(CH₃)₂,    —CH(CH₃)—CH₂—C(CH₃)₃, —CH₂—CH(CH₃)—C(CH₃)₃, —C_(8H17),    —C₄H₈—C(CH₃)₃, —C₅H₁₀—CH(CH₃)₂, —C₄H₈—CH(CH₃)—C₂H₅,    —C₃H₆—C(CH₃)₂—C₂H₅, —C₃H₆—CH(CH₃)—C₃H₇, —C₂H₄—C(CH₃)₂—C₃H₇,    —C₂H₄—CH(CH₃)—C₄H₉, —CH₂—CH(CH₃)—C₅H₁₁, —C(CH₃)₂—C₅H₁₁,    —CH(CH₃)—C₆H₁₃, —C₉H₁₉, —C₅H₁₀—C(CH₃)₃, —C₆H₁₂—CH(CH₃)₂,    —C₅H₁₀—CH(CH₃)—C₂H₅, —C₄H₈—C(CH₃)₂—C₂H₅, —C₄H₈—C(CH₃)—C₃H₇,    —C₃H₆—C(CH₃)₂—C₃H₇, —C₃H₆—CH(CH₃)—C₄H₉, —C₂H₄—C(CH₃)₂—C₄₉,    —C₂H₄—CH(CH₃)—C₅H₁₁, —CH₂—C(CH₃)₂—C₅H₁₁, —CH₂—CH(CH₃)—C₆H₁₃,    —C(CH₃)₂—C₆H₁₃, —CH(CH₃)—C₇H₁₅, —C₁₀H₂₁, —C₆H₁₂—C(CH₃)₃,    —C₇H₁₄—CH(CH₃)₂, —C₆H₁₂—CH(CH₃)—C₂H₅, —C₅H₁₀—C(CH₃)₂—C₂H₅,    —C₅H₁₀—CH(CH₃)—C₃H₇, —C₄H₈—C(CH₃)₂—C₃H₇, —C₄H₈—CH(CH₃)—C₄H₉,    —C₃H₆—C(CH₃)₂—C₄H₉, —C₃H₆—CH(CH₃)—C₅H₁₁, —C₂H₄—C(CH₃)₂—C₅H₁₁,    —C₂H₄—CH(CH₃)—C₆H₁₃, —CH₂—C(CH₃)₂—C₆H₁₃, —CH₂—CH(CH₃)—C₇H₁₅,    —C(CH₃)₂—C₇H₁₅, —CH(CH₃)—C₈H₁₇, —C₁₁H₂₃, —C₇H₁₄—C(CH₃)₃,    —C₈H₁₆—CH(CH₃)₂, —C₇H₁₄—CH(CH₃)—C₂H₅, —C₆H₁₂—C(CH₃)₂—C₂H₅,    —C₆H₁₂—CH(CH₃)—C₃H₇, —C₅H₁₀—C(CH₃)₂—C₃H₇, —C₅H₁₀—CH(CH₃)—C₄H₉,    —C₄H₈—C(CH₃)₂—C₄H₉, —C₄H₈—CH(CH₃)—C₅H₁₁, —C₃H₆—C(CH₃)₂—C_(5H11),    —C_(3H6)—CH(CH₃)—C₆H₁₃, —C₂H₄—C(CH₃)₂—C₆H₁₃, —C₂H₄—CH(CH₃)—C₇H₁₅,    —CH₂—C(CH₃)₂—C₇H₁₅, —CH₂—CH(CH₃)—C₈H₁₇, —C(CH₃)₂—C₈H₁₇,    —CH(CH₃)—C₉H₁₉, —C₁₂H₂₅, —C₈H₁₆—C(CH₃)₃, —C₉H₁₈—CH(CH₃)₂,    —C₈H₁₆—CH(CH₃)—C₂H₅, —C₇H₁₄—C(CH₃)₂—C₂H₅, —C₇H₁₄—CH(CH₃)—C₃H₇,    —C₆H₁₂—C(CH₃)₂—C₃H₇, —C₆H₁₂—CH(CH₃)—C₄H₉, —C₅H₁₀—C(CH₃)₂—C₄H₉,    —C₅H₁₀—CH(CH₃)—C₅H₁₁, —C₄H₈—C(CH₃)₂—C₅H₁₁, —C₄H₈—CH(CH₃)—C₆H₁₃,    —C₃H₆—C(CH₃)₂—C₆H₁₃, —C₃H₆—CH(CH₃)—C₇H₁₅, —C₂H₄—C(CH₃)₂—C₇H₁₅,    —C₂H₄—CH(CH₃)—C₈H₁₇, —CH₂—C(CH₃)₂—C₈H₁₇, —CH₂—CH(CH₃)—C₉H₁₉,    —C(CH₃)₂—C₉H₁₉, —CH(CH₃)—C₁₀H₂₁;-   R⁶ is independently of each other —H, —F, —Cl, —Br, —I, —NO₂,    —NR⁴R⁵, —CN, alkyl, cycloalkyl, —OH, alkoxy, alkylthio,    hydroxyalkylamino, haloalkyl, haloalkyloxy, hydroxyalkyl, aryl or    heteroaryl;-   R⁷ is independently of each other —H, —F, —Cl, —Br, —I, —NO₂,    —NR⁴R⁵, —CN, alkyl, cycloalkyl, —OH, alkoxy, alkylthio,    hydroxyalkylamino, haloalkyl, haloalkyloxy, hydroxyalkyl, aryl or    heteroaryl;-   R⁸ is independently of each other —H, —F, —Cl, —Br, —I, —NO₂,    —NR⁴R⁵, —CN, alkyl, cycloalkyl, —OH, alkoxy, alkylthio,    hydroxyalkylamino, haloalkyl, haloalkyloxy, hydroxyalkyl, aryl or    heteroaryl;-   X is selected from the group consisting of S, O, N, NR⁴, SO or SO₂;-   R⁴ is H, alkyl, cycloalkyl, aryl or heteroaryl;-   R⁵ is H, O-alkyl, O-aryl, alkyl, heteroaryl or aryl;-   R³, R^(3′) or R^(3″) are independently H, OR⁴, SR⁴, hydroxyalkyl,    hydroxyalkylamino, cycloalkyl, halogen, haloalkyl, haloalkyloxy,    NO₂, CN, SO₂NR⁴R⁵, CO₂NR⁴R⁵, COR⁴, CO₂R⁴, SO₂R⁴, SO₃R⁴, NR⁴R⁵, alkyl    aryl or heteroaryl; with R⁴, R⁵ being as defined above;-   an alkyl group, if not stated otherwise, denotes a linear or    branched C₁-C₆-alkyl, preferably a linear or branched chain of one    to five carbon atoms, a linear or branched C₁-C₆-alkenyl or a linear    or branched C₁-C₆-alkinyl group, which can optionally be substituted    by one or more substituents R³, preferably by halogen;-   the C₁-C₆-alkyl, C₁-C₆-alkenyl and C₁-C₆-alkinyl residue may be    selected from the group comprising —CH₃, —C₂H₅, —CH═CH₂, —C≡CH,    —C₃H₇, —CH(CH₃)₂, —CH₂—CH═CH₂, —C(CH₃)═CH₂, —CH═CH—CH₃, —C≡C—CH₃,    —CH₂—C≡CH, —C₄H₉, —CH₂—CH(CH₃)₂, —CH(CH₃)—C₂H₅, —C(CH₃)₃, —C₅H₁₁,    —C₆H₁₃, —C(R³)₃, —CR(R^(3′))₂, —CR³(R^(3′))R^(3″), —C₂(R³)₅,    —CH₂—C(R³)₃, —CH₂—CR³(R^(3′))₂, —CH₂—CR³(R^(3′))R^(3″), —C₃(R³)₇,    —C₂H₄—C(R³)₃, —C₂H₄—CH═CH₂, —CH═CH—C₂H₅, —CH═C(CH₃)₂,    —CH₂—CH═CH—CH₃, —CH═CH—CH═CH₂, —C₂H₄—C≡CH, —C≡C-c₂H₅, —CH₂—CH≡C—CH₃,    —C≡C—CH═CH₂, —CH═CH—C≡CH, —C≡C—C≡CH, —C₂H₄—CH(CH₃)₂, —CH(CH₃)—C₃H₇,    —CH₂—CH(CH₃)—C₂H₅, —CH(CH₃)—CH(CH₃)₂, —C(CH₃)₂—C₂H₅, —CH₂—C(CH₃)₃,    —C₃H₆—CH═CH₂, —CH═CH—C₃H₇, —C₂H₄—CH═CH—CH₃, —CH₂—CH═CH—C₂H₅,    —CH₂—CH═CH—CH═CH₂, —CH═CH—CH═CH—CH₃, —CH═CH—CH₂—CH═CH₂,    —C(CH₃)═CH—CH═CH₂, —CH═C(CH₃)—CH═CH₂, —CH═CH—C(CH₃)═CH₂,    —CH₂—CH═C(CH₃)₂, —C(CH₃)═C(CH₃)₂, —C₃H₆—C≡CH, —C≡C—C₃H₇,    —C₂H₄—C≡C—CH₃, —CH₂—C≡C—C₂H₅, —CH₂—C≡C—CH═CH₂, —CH₂—CH═CH—C≡CH,    —CH₂—C≡C—C≡CH, —C≡C—CH═CH—CH₃, —CH═CH—C≡C—CH₃, —C≡C—C≡C—CH₃,    —C≡C—CH₂—CH═CH₂, —CH═CH—CH₂—C≡CH, —C≡C—CH₂—C≡CH, —C(CH₃)═CH—CH═CH₂,    —CH═C(CH₃)—CH═CH₂, —CH═CH—C(CH₃)═CH₂, —C(CH₃)═CH—C≡CH,    —CH═C(CH₃)—C≡CH, —C≡C—C(CH₃)═CH₂, —C₃H₆—CH(CH₃)₂,    —C₂H₄—CH(CH₃)—C₂H₅, —CH(CH₃)—C₄H₉, —_(CH2)—CH(CH₃)—C₃H₇,    —CH(CH₃)—CH₂—CH(CH₃)₂, —CH(CH₃)—CH(CH₃)—C₂H₅, —CH₂—CH(CH₃)—CH(CH₃)₂,    —CH₂—C(CH₃)₂—C₂H₅, —C(CH₃)₂—C₂H₇, —C(CH₃)₂—CH(CH₃)₂, —C₂H₄—C(CH₃)₃,    —CH(CH₃)—C(CH₃)₃, —C₄H₈—CH═CH₂, —CH═CH—C₄H₉, —C₃H₆—CH═CH—CH₃,    —CH₂—CH═CH—C₃H₇, —C₂H₄—CH═CH—C₂H₅, —CH₂—C(CH₃)═C(CH₃)₂,    —C₂H₄—CH═C(CH₃)₂, —C₄H₈—C≡CH, —C≡C₄H₉, —C₃H₆—C≡C—CH₃, —CH₂—C≡C—C₃H₇,    —C₂H₄—C≡C—C₂H₅;-   a cycloalkyl group denotes a non-aromatic ring system containing    three to eight carbon atoms, preferably four to eight carbon atoms,    wherein one or more of the carbon atoms in the ring can be    substituted by a group X, X being as defined above; the    C₃-C₈-cycloalkyl residue may be selected from the group comprising    -cyclo-C₃H₅, -cyclo-C₄H₇, -cyclo-C₅H₉, -cyclo-C₆H₁₁, -cyclo-C₇H₁₃,    -cyclo-C₈H₁₅;-   an alkoxy group denotes an O-alkyl group, the alkyl group being as    defined above; the alkoxy group is preferably a methoxy, ethoxy,    isopropoxy, t-butoxy or pentoxy group.-   an haloalkyl group denotes an alkyl group which is substituted by    one to five halogen atoms, the alkyl group being as defined above;    the haloalkyl group is preferably a —C(R¹⁰)₃, —CR¹⁰(R^(10′))₂,    —CR¹⁰(R^(10′))R^(10″), —C₂(R¹⁰)₅, —CH₂—C(R¹⁰)₃, —CH₂—CR¹⁰(R^(10′))₂,    —CH₂—CR¹⁰(R^(10′))R^(10″), —C₃(R¹⁰)₇ or —C₂H₄—C(R¹⁰)₃, wherein R¹⁰,    R^(10′), R^(10″) represent F, Cl, Br or I, preferably F;-   a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group    being as defined above:-   an haloalkyloxy group denotes an alkoxy group which is substituted    by one to five halogen atoms, the alkyl group being as defined    above; the haloalkyloxy group is preferably a —OC(R¹⁰)₃,    —OCR¹⁰(R^(10′))₂, —OCR¹⁰(R^(10′))R^(10″), —OC₂(R¹⁰)₅, —OCH₂—C(R¹⁰)₃,    —OCH₂—CR¹⁰(R^(10′))₂, —OCH₂—CR¹⁰(R^(10′))R^(10″), —OC₃(R¹⁰)₇ or    —OC₂H₄—C(R¹⁰)₃, wherein R¹⁰, R^(10′), R^(10″) represent F, Cl, Br or    I, preferably F;-   a hydroxyalkylamino group denotes an (HO-alkyl)₂-N-group or    HO-alkyl-NH-group, the alkyl group being as defined above;-   a halogen group is chlorine, bromine, fluorine or iodine;-   an aryl group preferably denotes an aromatic group having five to    fifteen carbon atoms, which can optionally be substituted by one or    more substituents R³, where R³ is as defined above, the aryl group    is preferably a phenyl group, —CH₂—C₆H₄, —C₂H₄—C₆H₄, —CH═CH—C₆H₄,    —C≡C—C₆H₄, -o-C₆H₄—R³, -m-C₆H₄—R³, -p-C₆H₄—R³, -o-CH₂—C₆H₄R³,    -m-CH₂—C₆H₄—R³, -p-CH₂—C₆H₄—R³;-   a heteroaryl group denotes a 5- or 6-membered heterocyclic group    which contains at least one heteroatom like O, N, S. This    heterocyclic group can be fused to another ring. For example, this    group can be selected from an oxazol-2-yl, oxazol-4-yl, oxazol-5-yl,    thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl,    isothiazol-4-yl, isothiazol-5-yl, 1,2,4-oxadiazol-3-yl,    1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl,    1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl, 1,2,5-thiadiazol-3-yl,    1-imidazolyl, 2-imidazolyl, 1,2,5-thiadiazol-4-yl, 4-imidazolyl,    1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl,    3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl,    4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl,    2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, indolyl,    indolinyl, benzo-[b]-furanyl, benzo[b]thiophenyl, benzimidazolyl,    benzothiazolyl, quinazolinyl, quinoxazolinyl, or preferably    isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, quinolinyl,    tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl group.    This heterocyclic group can optionally be substituted by one or more    substituents R³, where R³ is as defined above.

However, the following compounds are excluded from Formula (X):

-   2-thiophenecarboxylic acid-5-nitro-2-(2-thienylcarbonyl)hydrazide,    4butylthiophene-2-carboxylic    acid-N′-(4-butyl-thiophen-2-carbonyl)hydrazide,    2-thiophenecarboxylic acid-3-chloro-2-(2-thienylcarbonyl)hydrazide,    2-thiophene carboxylic acid-5-bromo-2-(2-thienylcarbonyl)hydrazide,    1H-pyrazole-5-carboxylic    acid-1-methyl-2-(2-thienylcarbonyl)hydrazide, 2-thiophenecarboxylic    acid-5-(4,5,6,7-tetrahydro-benzo[b]thien-2-yl)-2-[[5-(4,5,6,7-tertahydrobenzo[b]thien-2-yl)-2-thienyl]-carbonyl]-hydrazide,    1H-pyrrole-2-carboxylic acid-2-(2-thienylcarbonyl)hydrazide,    2-thiophenecarboxylic acid-2-(2-thienylcarbonyl)-hydrazide,    2-thiophenecarboxylic acid N′-(furan-2-carbonyl)hydrazide,    2-thiophenecarboxylic acid-N-(5-bromofuran-2-carbonyl)hydrazide,    1H-pyrazole-3-carboxylic    acid-4-bromo-1,5-dimethyl-2-(2-thienylcarbonyl)hydrazide,    thiophene-2-carboxylic acid    N′-(3-chloro-4-methylthiophene-2-carbonyl)hydrazide and    2-furancarboxylic    acid-5-[[[4-methyl-6-(trifluoromethyl)-2-pyrimidinyl]thio]methyl]-2-(2-thienylcarbonyl)hydrazide.    Furthermore the present invention is directed to novel compounds of    the general Formula (X) and pharmaceutically acceptable salts    thereof:

wherein

-   A³ is an optionally substituted C₃-C₂₀-alkyl group or

-   with the C₃-C₂₀-alkyl group being as defined above for Formula (X)-   R³ is defined as above in Formula (X)-   R⁴ is defined as above in Formula (X)-   R⁵ is defined as above in Formula (X)-   R⁶ is independently of each other —H, —F, —Cl, —Br, —I, —NR⁴R⁵,    C₁-C₃-alkyl, alkoxy, alkylthio, hydroxyalkylamino, —CN, —NO₂, —OH,    haloalkyl, haloalkyloxy, hydroxyalkyl, aryl or heteroaryl;-   said C₁-C₃-alkyl of R⁶ denotes a linear or branched C₁-C₃-alkyl, a    linear or branched C₁-C₃-alkenyl or a linear or branched    C₁-C₃-alkinyl group, which can optionally be substituted by one or    more substituents R′, preferably by halogen; the C₁-C₃-alkyl,    C₁-C₃-alkenyl and C₁-C₃-alkinyl residue may be selected from the    group comprising —CH₃, —C₂H₅, —CH═CH₂, —≡CH, —C₃H₇, —CH(CH₃)₂,    —C≡C—CH₃, —CH₂—C≡CH;-   R⁷ is independently H, OR⁴, hydroxyalkyl, hydroxyalkylamino,    cycloalkyl, halogen, haloalkyl, haloalkyloxy, NO₂, CN, SO₂NR⁴R⁵,    CO₂NR⁴R⁵, COR⁴, CO₂R⁴, SO₂R⁴, SO₃R⁴, NR⁴R⁵, alkyl, aryl or    heteroaryl;-   R⁷ is independently of each other —H, —F, —Cl, —I, —NO₂, —NR⁴R⁵,    —CN, C₂-C₆-alkyl, cycloalkyl, —OH, alkoxy, alkylthio,    hydroxyalkylamino, haloalkyl, haloalkyloxy, hydroxyalkyl, aryl or    heteroaryl;-   said C₂-C₆-alkyl of R⁷, denotes a linear or branched C₂-C₆-alkyl, a    linear or branched C₂-C₆-alkenyl or a linear or branched    C₁-C₆-alkinyl group, which can optionally be substituted by one or    more substituents R³, preferably by halogen; the C₂-C₆-alkyl,    C₂-C₆-alkenyl and C₂-C₆-alkinyl residue may be selected from the    group comprising —C₂H₅, —CH═CH₂, —C≡CH, —C₃H₇, —CH(CH₃)₂, —C≡C—CH₃,    —CH₂—C≡CH, —CH₂—CH═CH₂, —C(CH₃)═CH₂, —CH═CH—CH₃, —C₄H₉,    —CH₂—CH(CH₃)₂, —CH(CH₃)—C₂H₅, —C(CH₃)₃, —C₅H₁₁, —C₆H₁₃, —C(R³)₃,    —CR³(R^(3′))₂, —CR³(R^(3′))R^(3″), —C₂(R³)₅, —CH₂—C(R³)₃,    —CH₂—CR³(R^(3′))₂, —CH₂—CR³(R^(3′))R^(3″), —C₃(R³)₇, —C₂H₄—C(R³)₃,    —C₂H₄—CH═CH₂, —CH═CH—C₂H₅, —CH═C(CH₃)₂, —CH₂—CH═CH—CH₃,    —CH═CH—CH═CH₂, —C₂H₄—C≡CH₂, —C≡C—C₂H₅, —CH₂—C≡C—CH₃, —C≡C—CH═CH₂,    —CH═CH—C≡CH, —C≡C—C≡CH, —C₂H₄—CH(CH₃)₂, —CH(CH₃)—C₃H₇,    —CH₂—CH(CH₃)—C₂H₅, —CH(CH₃)—CH(CH₃)₂, —C(CH₃)₂—C₂H₅, —CH₂—C(CH₃)₃,    —C₃H₆—CH═CH₂, —CH═CH—C₃H₇, —C₂H₄—CH═CH—CH₃, —CH₂—CH═CH—C₂H₅,    —CH₂—CH═CH—CH═CH₂, —CH═CH—CH═CH—CH₃, —CH═CH—CH₂—CH═CH₂,    —C(CH₃)═CH—CH═CH₂, —CH═C(CH₃)—CH═CH₂, —CH═CH—C(CH₃)═CH₂,    —CH₂—CH═C(CH₃)₂, —C(CH₃)═C(CH₃)₂, —C₃H₆—C≡CH, —C≡C—C₃H₇,    —C₂H₄—C≡C—CH₃, —CH₂—C≡C—C₂H₅, —CH₂—C≡C—CH═CH₂, —CH₂—CH═CH—C≡CH,    —CH₂—C≡C—C≡CH, —C≡C—CH═CH—CH₃, —CH═CH—C≡C—CH₃, —C≡C—C≡C—CH₃,    —C≡C—CH₂—CH═CH₂, —CH═CH—CH₂—C≡CH, —C≡C—CH₃—C≡CH, —C(CH₃)═CH—CH═CH₂,    —CH═C(CH₃)—CH═CH₂, —CH═CH—C(CH₃)═CH₂, —C(CH₃)═CH—C≡CH,    —CH═C(CH₃)—C≡CH, —C≡C—C(CH₃)═CH₂, —C₃H₆—CH(CH₃)₂,    —C₂H₄—CH(CH₃)—C₂H₅, —CH(CH₃)—C₄H₉, —CH₂—CH(CH₃)—C₃H₇,    —CH(CH₃)—CH₂—CH(CH₃)₂, —CH(CH₃)—CH(CH₃)—C₂H₅, —CH₂—CH(CH₃)—CH(CH₃)₂,    —CH₂—C(CH₃)₂—C₂H₅, —C(CH₃)₂—C₃H₇, —C(CH₃)₂—CH(CH₃)₂, —C₂H₄—C(CH₃)₃,    —CH(CH₃)—C(CH₃)₃, —C₄H₈—CH═CH₂, —CH═CH—C₄H₉, —C₃H₆—CH═CH—CH₃,    —CH₂—CH═CH—C₃H₇, —C₂H₄—CH═CH—C₂H₅, —CH₂—C(CH₃)═C(CH₃)₂,    —C₂H₄—CH═C(CH₃)₂, —C₄H₈—C≡CH, —C≡C—C₄H₉, —C₃H₆—C≡C—CH₃,    —CH₂—C≡C—C₃H₇, —C₂H₄—C≡C—C₂H₅;-   R³, R^(3′) or R^(3′) are defined as above in Formula (X)-   R⁴, R⁵ are defined as above in Formula (X);-   R⁸ is independently of each other —H, —′F, —I, —NR⁴R⁵, —CN,    C₁-C₃-alkyl, —OH, alkoxy, alkylthio, hydroxyalkylamino, haloalkyl,    haloalkyloxy, hydroxyalkyl, aryl or heteroaryl;-   said C₁-C₃-alkyl of R⁸, denotes a linear or branched C₁-C₃-alkyl, a    linear or branched C₁-C₃-alkenyl or a linear or branched    C₁-C₃-alkinyl group, which can optionally be substituted by one or    more substituents R′, preferably by halogen; the C₁-C₃-alkyl,    C₁-C₃-alkenyl and C₁-C₃-alkinyl residue may be selected from the    group comprising —CH₃, —C₂H₅, —CH═CH₂, C≡CH, —C₃H₇, —CH(CH₃)₂,    —C≡C—CH₃, —CH₂—C≡CH;-   R′ is defined as above in Formula (X);-   R⁴, R⁵ are defined as above in Formula (X);-   R⁸ is independently of each other —F, —I, —NR⁴R⁵, —CN, C₁-C₃-alkyl,    —OH, alkoxy, alkylthio, hydroxyalkylamino, haloalkyl, haloalkyloxy,    hydroxyalkyl, aryl or heteroaryl;-   said C₁-C₃-alkyl of R^(8′), denotes a linear or branched    C₁-C₃-alkyl, a linear or branched C₁-C₃-alkenyl or a linear or    branched C₁-C₃-alkinyl group, which can optionally be substituted by    one or more substituents R′, preferably by halogen; the C₁-C₃-alkyl,    C₁-C₃-alkenyl and C₁-C₃-alkinyl residue may be selected from the    group comprising —CH₃, —C₂H₅, —CH═CH₂, —C≡CH, —C₃H₇, —CH(CH₃)₂,    —C≡C—CH₃, —CH₂—C≡CH;-   R′ is defined as above in Formula (X);-   an alkyl group, referring to R³, R^(3′), R^(3″), R⁴ or R⁵ denotes a    linear or branched C₁-C₆-alkyl, preferably a linear or branched    chain of 1 to 5 carbon atoms, a linear or branched C₁-C₆-alkenyl or    a linear or branched C₁-C₆-alkinyl group, which can optionally be    substituted by one or more substituents R³, preferably by halogen;-   the C₁-C₆-alkyl, C₁-C₆-alkenyl and C₁-C₆-alkinyl residue may be    selected from the group comprising —CH₃, —C₂H₅, —CH═CH₂, —C≡CH,    —C₃H₇, —CH(CH₃)₂, —CH₂—CH═CH₂, —C(CH₃)═CH₂, —CH═CH—CH₃, —C≡C—CH₃,    —CH₂—C≡CH, —C₄H₉, —CH₂—CH(CH₃)₂, —CH(CH₃)—C₂H₅, —C(CH₃)₃, —C₅H₁₁,    —C₆H₁₃, —C(R³)₃, —CR³(R^(3′))₂, —CR³(R^(3′))R^(3″), —C₂(R³)₅,    —CH₂—C(R³)₃, —CH₂—CR³(R^(3′))₂, —CH₂—CR³(R^(3′))R^(3″), —C₃(R³)₇,    —C₂H₄—C(R³)₃, —C₂H₄—CH═CH₂, —CH═CH—C₂H₅, —CH═C(CH₃)₂,    —CH₂—CH═CH—CH₃, —CH═CH—CH═CH₂, —C₂H₄—C≡CH, —C≡C—C₂H₅, —CH₂—C≡C—CH₃,    —C≡C—CH═CH₂, —CH═CH—C≡CH, —C≡C—C≡CH, —C₂H₄—CH(CH₃)₂, —CH(CH₃)—C₃H₇,    —CH₂—CH(CH₃)—C₂H₅, —CH(CH₃)—CH(CH₃)₂, —C(CH₃)₂—C₂H₅, —CH₂—C(CH₃)₃,    —C₃H₆—CH═CH₂, —CH═CH—C₃H₇, —C₂H₄—CH═CH—CH₃, —CH₂—CH═CH—C₂H₅,    —CH₂—CH═CH—CH═CH₂—, —CH═CH—CH═CH—CH₃, —CH═CH—CH₂—CH═CH₂,    —C(CH₃)═CH—CH═CH₂, —CH═C(CH₃)—CH═CH₂, —CH═CH—C(CH₃)═CH₂,    —CH₂—CH═C(CH₃)₂, —C(CH₃)═C(CH₃)₂, —C₃H₆—C≡CH, —C≡C—C₃H₇,    —C₂H₄—C≡C—CH₃, —CH₂—C≡C—C₂H₅, —CH₂—C≡C—CH═CH₂, —CH₂—CH═CH—C≡CH,    —CH₂—C≡C—C≡CH, —C≡C—CH═CH—CH₃, —CH═CH—C≡C—CH₃, —C≡C—C≡C—CH₃,    —C≡C—CH₂—CH═CH₂, —CH═CH—CH₂—C≡CH, —C≡C—CH₂—C—CH, —C(CH₃)═CH—CH═CH₂,    —CH═C(CH₃)—CH═CH₂, —CH═CH—C(CH₃)═CH₂, —C(CH₃)═CH—C≡CH,    —CH═C(CH₃)—C≡CH, —C≡C—C(CH₃)═CH₂, —C₃H₆—CH(CH₃)₂,    —C₂H₄—CH(CH₃)—C₂H₅, —CH(CH₃)—C₄H₉, —CH₂—CH(CH₃)—C₃H₇,    —CH(CH₃)—CH₂—CH(CH₃)₂, —CH(CH₃)—CH(CH₃)—C₂H₅, —CH₂—CH(CH₃)—CH(CH₃)₂,    —CH₂—C(CH₃)₂—C₂H₅, —C(CH₃)₂—C₃H₇, —C(CH₃)₂—CH(CH₃)₂, —C₂H₄—C(CH₃)₃,    —CH(CH₃)—C(CH₃)₃, —C₄H₈—CH═CH₂, —CH═CH—C₄H₉, —C₃H₆—CH═CH—CH₃,    —CH₂—H═CH—C₃H₇, —C₂H₄—CH═CH—C₂H₅, —CH₂—C(CH₃)═C(CH₃)₂,    —C₂H₄—CH═C(CH₃)₂, —C₄H₈—C≡CH, —C≡C—C₄H₉, —C₃H₆—C≡C—CH₃,    —CH₂—C≡C—C₃H₇, —C₂H₄—C≡C—C₂H₅;-   R³, R^(3′) or R^(3″) are defined as above in Formula (X);-   a cycloalkyl group is defined as above in Formula (X);-   an alkoxy group is defined as above in Formula (X);-   an haloalkyl is defined as above for in Formula (X);-   a hydroxyalkyl group is defined as above in Formula (X);-   an haloalkyloxy group is defined as above in Formula (X);-   a hydroxyalkylamino group is defined as above in Formula (X);-   a halogen group is defined as above in Formula (X);-   an aryl group is defined as above in Formula (X);-   a heteroaryl group is defined as above in Formula (X).

Furthermore the present invention is directed to novel compounds of thegeneral Formula (XI) and pharmaceutically acceptable salts thereof:

wherein

-   A⁴ is an optionally substituted C₂-C₂₀-alkyl or a 5-membered    heteroaryl group, which contains at least one heteroatom like O, N,    S, NR⁴, SO, SO₂, Se; which can optionally be substituted by one or    more substituents R³;-   R³ is independently H, OR⁴, SR⁴, hydroxyalkyl, hydroxyalkylamino,    cycloalkyl, halogen, haloalkyl, haloalkyloxy, NO₂, CN, SO₂NR⁴R⁵,    CO₂NR⁴R⁵, COR⁴, CO₂R⁴, SO₂R⁴, SO₃R⁴, NR⁴R⁵, alkyl, aryl or    heteroaryl;-   R⁴ is H, alkyl, cycloalkyl, aryl or heteroaryl;-   R⁵ is H, O-alkyl, O-aryl, alkyl, heteroaryl or aryl;-   R¹⁷ is independently of each other —H, —F, —Cl, —I, —NO₂, —NR⁴R⁵,    —CN, alkyl, cycloalkyl, —OH, alkoxy, alkylthio, hydroxyalkylamino,    haloalkyl, haloalkyloxy, hydroxyalkyl, aryl or heteroaryl;-   said C₂-C₁₀-alkyl residue may be selected from the group comprising    —C₂H₅, —C₃H₇, —CH(CH₃)₂, —C₄H₉, —CH₂—CH(CH₃)₂, —CH(CH₃)—C₂H₅,    —C(CH₃)₃, —C₅H₁₁, —C₂H₄—CH(CH₃)₂, —CH(CH₃)—C₃H₇, —CH₂—CH(CH₃)—C₂H₅,    —CH(CH₃)—CH(CH₃)₂, —C(CH₃)₂—C₂H₅, —CH₂—C(CH₃)₃, —C₆H₁₃,    —C₃H₆—CH(CH₃)₂, —C₂H₄—CH(CH₃)—C₂H₅, —CH(CH₃)—C₄H₉,    —CH₂—CH(CH₃)—C₃H₇, —CH(CH₃)—CH₂—CH(CH₃)₂, —CH(CH₃)—CH(CH₃)—C₂H₅,    —CH₂—CH(CH₃)—CH(CH₃)₂, —CH₂—C(CH₃)₂—C₂H₅, —C(CH₃)₂—C₃H₇,    —C(CH₃)₂—CH(CH₃)₂, —C₂H₄—C(CH₃)₃, —CH(CH₃)—C(CH₃)₃, —C₇H₁₅,    —C₃H₆—C(CH₃)₃, —C₄H₈—CH(CH₃)₂, —C₃H₆—CH(CH₃)—C₂H₅,    —C₂H₄—C(CH₃)₂—C₂H₅, —C₂H₄—CH(CH₃)—C₃H₇, —CH₂—C(CH₃)₂—C₃H₇,    —CH₂—CH(CH₂)—C₄H₉, —CH(CH₂)—C₅H₁₁, —C₈H₁₇, —C₄H₈—C(CH₃)₃,    —C₅H₁₀—CH(CH₃)₂, —C₄H₈—CH(CH₃)—C₂H₅, —C₃H₆—C(CH₃)₂—C₂H₅,    —C₃H₆—CH(CH₃)—C₃H₇, —C₂H₄—C(CH₃)₂—C₃H₇, —C₂H₃—CH(CH₃)—C₄H₉,    —CH₂—C(CH₃)₂—C₄H₉, —CH₂—CH(CH₃)—C₅H₁₁, —C(CH₃)₂—C₅H₁₁,    —CH(CH₃)—C₆H₁₃, —C₉H₁₉, —C₅H₁₀—C(CH₃)₃, —C₆H₁₂—CH(CH₃)₂,    —C₅H₁₀—CH(CH₃)—C₂H₅, —C₄H₈—C(CH₃)₂—C₂H₅, —C₄H₈—CH(CH₃)—C₃h₇,    —C₃H₆—C(CH₃)₂—C₃H₇, —C₃H₆—CH(CH₃)—C₄H₉, —C₂H₄—C(CH₃)₂—C₄H₉,    —C₂H₄—CH(CH₃)—C₅H₁₁, —CH₂—C(CH₃)₂—C₅H₁₁, —CH₂—CH(CH₃)—C₆H₁₃,    —C(CH₃)₂—C₆H₁₃, —CH(CH₃)—C₇H₁₅, —C₁₀H₂₁, —-C₆H₁₂—C(CH₃)₃,    —C₇H₁₄—CH(CH₃)₂, —C₆H₁₂—CH(CH₃)—C₂H₅, —C₅H₁₀—C(CH₃)₂—C₂H₅,    —C₅H₁₀—CH(CH₃)—C₃H₇, —C₄H₈—C(CH₃)₂—C₃H₇, —C₄H₈—CH(CH₃)—C₄H₉,    —C₃H₆—C(CH₃)₂—C₄H₉, —C₃H₆—CH(CH₃)—C₅H₁₁, —C₂H₄—C(CH₃)₂—C₅H₁₁,    —C₂H₄—CH(CH₃)—C₆H₁₃, —CH₂—C(CH₃)₂—C₆H₁₃, —CH₂—CH(CH₃)—C₇H₁₅,    —C(CH₃)₂—C₇H₁₅, —CH(CH₃)—C₈H₁₇, —C₁₁H₂₃, —C₇H₁₄—C(CH₃)₃,    —C₈H₁₆—CH(CH₃)₂, —C₇H₁₄—CH(CH₃)—C₂H₅, —C₆H₁₂—C(CH₃)₂—C₂H₅,    —C₆H₁₂—CH(CH₃)—C₃H₇, —C₅H₁₀—C(CH₃)₂—C₃H₇, —C₅H₁₀—CH(CH₃)—C₄H₉,    —C₄H₈—C(CH₃)₂—C₄H₉, —C₄H₈—CH(CH₃)—C₅H₁₁, —C₃H₆—C(CH₃)₂—C₅H₁₁,    —C₃H₆—CH(CH₃)—C₆H₁₃, —C₂H₄—C(CH₃)₂—C₆H₁₃, —C₂H₄—CH(CH₃)—C₇H₁₅,    —CH₂—C(CH₃)₂—C₇H₁₅, —CH₂—CH(CH₃)—C₈H₁₇, —C(CH₃)₂—C₈H₁₇,    —CH(CH₃)—C₉H₁₉, —C₁₂H₂₁, —C₈H₁₆—C(CH₃)₃, —C₉H₁₈—CH(CH₃)₂,    C₈H₁₆—CH(CH₃)—C₂H₅, —C₇H₁₄—C(CH₃)₂—C₂H₅, —C₇H₁₄—C(CH₃)—C₃H₇,    —C₆H₁₂—C(CH₃)₂—C₃H₇, —C₆H₁₂—CH(CH₃)—C₄H₉, —C₅H₁₀—C(CH₃)₂—C₄H₉,    —C₅H₁₀—CH(CH₃)—C₅H₁₁, —C₄H₈—C(CH₃)₂—C₅H₁₁, —C₄H₈—CH(CH₃)—C₆H₁₃,    —C₃H₆—C(CH₃)₂—C₆H₁₃, —C₃H₆—CH(CH₃)—C₇H₁₅, C₂H₄′C(CH₃)₂—C₇H₁₅,    —C₂H₄—CH(CH₃)—C₈H₁₇, CH₂—C(CH₃)₂—C₈H₁₇, —CH₂—CH(CH₃)—C₉H₁₉,    —C(CH₃)₂—C₉H₁₉, —CH(CH₃)—C₁₀H₂₁;-   an alkyl group, if not stated otherwise, denotes a linear or    branched C₁-C₆-alkyl, preferably a linear or branched chain of one    to live carbon atoms, a linear or branched C₁-C₆-alkenyl or a linear    or branched C₁-C₆-alkinyl group, which can optionally be substituted    by one or more substituents R³, preferably by halogen;-   the C₁-C₆-alkyl, C₁-C₆-alkenyl and C₁-C₆alkinyl residue may be    selected from the group comprising —CH₃, —C₂H₅, —CH═CH₂, —C≡CH,    —C₃H₇, —CH(CH₃)₂, —CH₂—CH═CH₂, —C(CH₃)═CH₂, —CH═CH—CH₃, —C≡C—CH₃,    —CH₂—C≡CH, —C₄H₉, —CH₂—CH(CH₃)₂, —CH(CH₃)—C₂H₅, —C(CH₃)₃, —C₅H₁₁,    —C₆H₁₃, —C(R³)₃, —CR³(R^(3′))₂, —CR³(R^(3′))R^(3″), —C₂(R³)₅,    —CH₂—C(R³)₃, —CH₂—CR³(R^(3′))₂, —CH₂—CR³(R^(3′))R^(3″), —C₃(R³)₇,    —C₂H₄—C(R³)₃, —C₂H₄—CH═CH₂, —CH═CH—C₂H₅, —CH═C(CH₃)₂,    —CH₂—CH═CH—CH₂, —CH═CH—CH═CH₂, —C₂H₄—C≡CH, —C≡C—C₂H₅, —CH₂—C≡C—CH₃,    —C≡C—CH═CH₂, —CH═CH—C≡CH, —C≡C—C≡CH, —C₂H₄—CH(CH₃)₂, —CH(CH₃)—C₃H₇,    —CH₂—CH(CH₃)—C₂H₅, —CH(CH₃)—CH(CH₃)₂, —C(CH₃)₂—C₂H₅, —CH₂—C(CH₃)₃,    —C₃H₆—CH═CH₂, —CH═CH—C₃H₇, —C₂H₄—CH═CH—CH₃, —CH₂—CH═CH—C₂H₅,    —CH₂—CH═CH—CH═CH₂, —CH═CH—CH═CH—CH₃, —CH═CH—CH₂—CH═CH₂,    —C(CH₃)═CH—CH═CH₂, —CH═C(CH₃)—CH═CH₂, —CH═CH—C(CH₃)CH₂,    —CH₂—CH═C(CH₃)₂, —C(CH₃)═C(CH₃)₂, —C₃H₆—C≡CH, —C≡C—C₃H₇,    —C₂H₄—C≡C—CH₃, —CH₂—C≡C—C₂H₅, —CH₂—C≡C—CH═CH₂, —CH₂—CH═CH—C≡CH,    —CH₂—C≡C—C≡CH, —C≡C—CH═CH—CH₃, —CH═CH—C≡C—CH₃, —C≡C—C≡C—CH₃,    —C≡C—C≡CH₃, —C≡C—CH₂—CH═CH₂, —CH═CH—CH₂—C≡CH, —C≡C—CH₂—C≡CH,    —C(CH₃)═CH—CH═CH₂, —CH═C(CH₃)—CH═CH₂, —CH═CH—C(CH₃)═CH₂,    —C(CH₃)═CH—C≡CH, —CH═C(CH₃)—C≡CH, —C≡C—C(CH₃)═CH₂, —C₃H₆—CH(CH₃)₂,    —C₂H₄—CH(CH₃)—C₂H₅, —CH(CH₃)—C₄H₉, —CH₂—CH(CH₃)—C₃H₇,    —CH(CH₃)—CH₂—CH(CH₃)₂, —CH(CH₃)C₂H₅, —CH₂—CH(CH₃)—CH(CH₃)₂,    —CH₂—C(CH₃)₂—C₂H₅, —C(CH₃)₂—C₃H₇, —C(CH₃)₂—CH(CH₃)₂, —C₂H₄—C(CH₃)₃,    —CH(CH₃)—C(CH₃)₃, —C₄H₈—CH═CH₂, —CH═CH—C₄H₉, —C₃H₆—CH═CH—CH₃,    —CH₂—CH═CH—C₃H₇, —C₂H₄—CH═CH—C₂H₅, —CH₂—(CH₃)═C(CH₃)₂,    —C₂H₄—CH═C(CH₃)₂, —C₄H₈—C≡CH, —C≡C—C₄H₉, —C₃H₆—C≡C—CH₃,    —CH₂—C≡C—C₃H₇, —C₂H₄—C≡C—C₂H₅;-   a cycloalkyl group denotes a non-aromatic ring system containing    three to eight carbon atoms, preferably four to eight carbon atoms,    wherein one or more of the carbon atoms in the ring can be    substituted by a group X, X being as defined above; the    C₃-C₈-cycloalkyl residue may be selected from the group comprising    -cyclo-C₃H₅, -cyclo-C₄H₇, -cyclo-C₅H₉, -cyclo-C₆H₁₁, -cyclo-C₇H₁₃,    -cyclo-C₈H₁₅;-   an alkoxy group denotes an O-alkyl group, the alkyl group being as    defined above, the alkoxy group is preferably a methoxy, ethoxy,    isopropoxy, t-butoxy or pentoxy group.-   an haloalkyl group denotes an alkyl group which is substituted by    one to five halogen atoms, the alkyl group being as defined above;    the haloalkyl group is preferably a —C(R¹⁰)₃, —CR¹⁰(R^(10′))₂,    —CR¹⁰(R^(10′))R^(10″), —C₂(R¹⁰)₅, —CH₂—C(R¹⁰)₃, —CH₂—CR¹⁰(R^(10′))₂,    —CH₂—CR¹⁰(R^(10′))R^(10″), —C₃(R¹⁰)₇ or —C₂H₄—C(R¹⁰)₃, wherein R¹⁰,    R^(10′), R^(10″) represent F, Cl, Br or I, preferably F;-   a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group    being as defined above;-   an haloalkyloxy group denotes an alkoxy group which is substituted    by one to five halogen atoms, the alkyl group being as defined    above; the haloalkyloxy group is preferably a —OC(R¹⁰)₃,    —OCR¹⁰(R^(10′))₂, —OCR¹⁰(R^(10′))R^(10″), —OC₂(R¹⁰)₅, —OCH₂—C(R¹⁰)₃,    —OCH₂—CR¹⁰(R^(10′))₂, —OCH¹⁰(R^(10′))R^(10″), —OC₃(R¹⁰)₇ or    —OC₂H₄—C(R¹⁰)₃, wherein R¹⁰, R^(10′), R^(10″) represent F, Cl, Br or    I, preferably F;-   a hydroxyalkylamino group denotes an (HO-alkyl)₂-N-group or    HO-alkyl-NH-group, the alkyl group being as defined above;-   a halogen group is chlorine, bromine, fluorine or iodine;-   an aryl group preferably denotes an aromatic group having five to    fifteen carbon atoms, which can optionally be substituted by one or    more substituents R³, where R³ is as defined above; the aryl group    is preferably a phenyl group, —CH₂—C₆H₄, —C₂H₄—C₆H₄, —CH═CH—C₆H₄,    —C≡C—C₆H₄, -o-C₆H₄—R³, -m-C₆H₄—R³, -p-C₆H₄—R³, -o-CH₂—C₆H₄—R³,    -m-CH₂—C₆H₄—R³, -p-CH₂—C₆H₄—R³;-   a heteroaryl group denotes a 5- or 6-membered heterocyclic group    which contains at least one heteroatom like O, N, S. This    heterocyclic group can be fused to another ring. For example, this    group can be selected from an oxazol-2-yl, oxazol-4-yl, oxazol-5-yl,    thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl,    isothiazol-4-yl, isothiazol-5-yl, 1,2,4-oxadiazol-3-yl,    1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl,    1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl, 1,2,5-thiadiazol-3-yl,    1-imidazolyl, 2-imidazolyl, 1,2,5-thiadiazol-4-yl, 4-imidazolyl,    1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl,    3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl,    4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl,    2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, indolyl,    indolinyl, benzo-[b]-furanyl, benzo[b]thiophenyl, benzimidazolyl,    benzothiazolyl, quinazolinyl, quinoxazolinyl, or preferably    isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, quinolinyl,    tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl group.    This heterocyclic group can optionally be substituted by one or more    substituents R³, where R³ is as defined above.-   with the proviso that    N-(1-methyl-1H-pyrazole-5-yl)-1H-pyrazole-1-carboxamide, and    1-ethyl-3-methyl-N-(1-methyl-1H-pyrazole-5-yl)-4-nitro-1H-pyrazole-5-carboxamide    are excluded.

Furthermore the present invention is directed to novel compounds of thegeneral Formula (XI) and pharmaceutically acceptable salts thereof,

wherein

-   A⁴ is an optionally substituted C₂-C₂₀-alkyl or a 5-membered    heteroaryl group, which contains at least one heteroatom like O, N,    S, NR⁴, SO, SO₂, Se; which can optionally be substituted by one or    more substituents R³;-   R³ is independently H, OR⁴, SR⁴, hydroxyalkyl, hydroxyalkylamino,    cycloalkyl, halogen, haloalkyl, haloalkyloxy, NO₂, CN, SO₂NR⁴R⁵,    CO₂NR⁴R⁵, COR⁴, CO₂R⁴, SO₂R⁴, SO₃R⁴, NR⁴R⁵, alkyl, aryl or    heteroaryl;-   R⁴ is H, alkyl, cycloalkyl, aryl or heteroaryl;-   R⁵ is H, O-alkyl, O-aryl, alkyl, heteroaryl or aryl;-   R¹⁷ is independently of each other —H, —F, —Cl, —I, —NO₂, —NR⁴R⁵,    —CN, alkyl, cycloalkyl, —OH, alkoxy, alkylthio, hydroxyalkylamino,    haloalkyl, haloalkyloxy, hydroxyalkyl, aryl or heteroaryl;-   said C₂-C₂₀-alkyl residue may be selected from the group given above    for C₂-C₂₀-alkyl residue of Formula (XI).-   a cycloalkyl group is defined as above in Formula (X);-   an alkoxy group is defined as above in Formula (X);-   an haloalkyl is defined as above for in Formula (X);-   a hydroxyalkyl group is defined as above in Formula (X);-   an haloalkyloxy group is defined as above in Formula (X);-   a hydroxyalkylamino group is defined as above in Formula (X);-   a halogen group is defined as above in Formula (X);-   an aryl group is defined as above in Formula (X);-   a heteroaryl group may be selected from the group comprising    oxazole2-yl, oxazol-4-yl, oxazole-5-yl, thiazole-2-yl,    thiazole-4-yl, thiazole-5-yl, isothiazole-3-yl, isothiazole-4-yl,    isothiazole-5-yl, 1,2,4-oxadiazole-3-yl, 1,2,4oxadiazole-5-yl,    1,2,4-thiadiazole-3-yl, 1,2,4-thiadiazole-5-yl,    1,2,5-oxadiazole-3-yl, 1,2,5-oxadiazole-4-yl,    1,2,5-thiadiazole-3-yl, 1-imidazolyl, 2-imidazolyl,    1,2,5-thiadiazol-4-yl, 4-imidazolyl, 1-pyrrolyl, 2-pyrrolyl,    3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 4-pyridyl,    4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl,    2-pyrazinyl, 3-pyrazolyl, 4-pyrazolyl, indolyl, indolinyl,    benzo[b]thiophenyl, benzimidazolyl, quinazolinyl, quinoxazolinyl,    preferably isoxazole-3-yl, isoxazole-4-yl, isoxazole-5-yl,    tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl group,    wherein said heteroaryl group can optionally be substituted by one    or more substituents R³, R³ being as defined above in Formula (XI).

Furthermore the present invention is directed to novel compounds of thegeneral Formula (XII) and pharmaceutically acceptable salts thereof:

wherein

-   R¹¹ is an optionally substituted phenyl group by one to five    substituents R⁹ or an optionally substituted C₄-C₂₀-alkyl group by    one or more substituents R³;-   R⁹ is independently of each other —H, —F, —Cl, —Br, —I, —SO₂NH⁴,    —SO₂N(R⁴)₂, —NR⁴R⁵, —NR⁴—CO—(C₁-C₆)-haloalkyl, —NO₂,    —NR⁴—SO₂—(C₁-C₆)-haloalkyl, —CN, alkyl, cycloalkyl, —OH, —SH,    alkylthio, alkoxy, hydroxyalkylamino, haloalkyloxy, haloalkyl,    hydroxyalkyl, aryl or heteroaryl;-   R¹⁰ is independently of each other —H, —F, —Cl, —Br, —I, —NO₂,    NR⁴R⁵, —CN, alkyl, —OH, cycloalkyl, —SH, alkylthio,    hydroxyalkylamino, hydroxyalkyl, aryl or heteroaryl;-   R³, R^(3′), R^(3″) is independently H, OR⁴, SR⁴, hydroxyalkyl,    hydroxyalkylamino, cycloalkyl, halogen, haloalkyl, haloalkyloxy,    NO₂, CN, SO₂NR⁴R⁵, CO₂NR⁴R⁵, COR⁴, CO₂R⁴, SO₂R⁴, SO₃R⁴, NR⁴R⁵,    alkyl, aryl or heteroaryl,-   R⁴ is H, alkyl, cycloalkyl, aryl or heteroaryl;-   R⁵ is H, O-alkyl, O-aryl, alkyl, heteroaryl or aryl;-   X is selected from the group consisting of S, O, N, NR⁴, SO or SO₂;-   said C₄-C₂₀-alkyl residue may be selected from the group comprising    —C₄H₉, —CH₂—CH(CH₃)₂, —CH(CH₃)—C₂H₅, —C(CH₃)₃, —C₅H₁₁,    —C₂H₄—CH(CH₃)₂, —CH(CH₃)—C₃H₇, —CH₂—CH(CH₃)—C₂H₅, —CH(CH₃)—CH(CH₃)₂,    —C(CH₃)₂—C₂H₅, —CH₂—C(CH₃)₃, —C₆H₁₃, —C₃H₆—CH(CH₃)₂,    —C₂H₄—CH(CH₃)—C₂H₅, —CH(CH₃)—C₄H₉, —CH₂—CH(CH₃)—C₃H₇,    —CH(CH₃)—CH₂—CH(CH₃)₂, —CH(CH₃)—CH(CH₃)—C₂H₅, —CH₂CH(CH₃)—CH(CH₃)₂,    —CH₂—C(CH₃)₂—C₂H₅, —C(CH₃)₂—C₃H₇, —C(CH₃)₂—CH(CH₃)₂, —C₂H₄—C(CH₃)₃,    —CH(CH₃)—C(CH₃)₃, —C₇H₁₅, —C₃H₆—C(CH₃)₃, —C₄H₈—CH(CH₃)₂,    —C₃H₆—CH(CH₃)—C₂H₅, —C₂H₄—C(CH₃)₂—C₂H₅, —C₂H₄—CH(CH₃)—C₃H₇,    —CH₂—C(CH₃)₂—C₃H₇, —CH₂—CH(CH₃)—C₄H₉, —CH(CH₃)—C₅H₁₁, —C₈H₁₇,    —C₄H₈—C(CH₃)₃, —C₅H₁₀—CH(CH₃)₂, —C₄H₈—CH(CH₃)—C₂H₅,    —C₃H₆—C(CH₃)₂—C₂H₅, —C₃H₆—CH(CH₃)—C₃H₇, —C₂H₄—C(CH₃)₂—C₃H₇,    —C₂H₄—CH(CH₃)—C₄H₉, —CH₂—C(CH₃)₂—C₄H₉, —CH₂—CH(CH₃)—C₅C₁₁,    —C(CH₃)₂—C₅H₁₁, —CH(CH₃)—C₆H₁₃, —C₉H₁₉, —C₅H₁₀—C(CH₃)₃,    —C₆H₁₂—CH(CH₃)₂, —C₅H₁₀—CH(CH₃)—C₂H₅, —C₄H₈—C(CH₃)₂—C₂H₅,    —C₄H₈—CH(CH₃)—C₃H₇, —C₃H₆—C(CH₃)₂—C₃H₇, —C₃H₆CH(CH₃)—C₄H₉,    —C₂H₄—C(CH₃)₂—C₄H₉, —C₂H₄—CH(CH₃)—C₅H₁₁, —CH₂—C(CH₃)₂—C₅H₁₁,    —CH₂—CH(CH₃)—C₆H₁₃, —C(CH₃)₂—C₆H₁₃, —CH(CH₃)—C₇H₁₅, —C₁₀H₂₁,    —C₆H₁₂—C(CH₃)₃, —C₇H₁₄—CH(CH₃)₂, —C₆H₁₂—CH(CH₃)—C₂H₅,    —C₅H₁₀—C(CH₃)₂—C₂H₅, —C₅H₁₀—CH(CH₃)—C₃H₇, —C₄H₈—C(CH₃)₂—C₃H₇,    —C₄H₈—CH(CH₃)—C₄H₉, —C₃H₆—C(CH₃)₂—C₄H₉, —C₃H₆—CH(CH₃)—C₅H₁₁,    —C₂H₄—C(CH₃)₂—C₅H₁₁, —C₂H₄—CH(CH₃)—C₆H₁₃, —CH₂—C(CH₃)₂—C₆H₁₃,    —CH₂—CH(CH₃)—C₇h₁₅, —C(CH₃)₂—C₇H₁₅, —CH(CH₃)—C₈H₁₇, —C₁₁H₂₃,    —C₇H₁₄—C(CH₃)₃, —C₈H₁₆—CH(CH₃)₂, —C₇H₁₄—CH(CH₃)—C₂H₅,    —C₆H₁₂—C(CH₃)₂—C₂H₅, —C₆H₁₂—CH(CH₃)—C₃₁H₇, —C₅H₁₀—C(CH₃)₂—C₃H₇,    —C₅H₁₀—CH(CH₃)—C₄H₉, —C₄H₈—C(CH₃)₂—C₄H₉, —C₄H₈—H(CH₃)—C₅H₁₁,    —C₃H₆—C(CH₃)₂—C₅H₁₁, —C₃h₆-CH(CH₃)—C₆H₁₃, —C₂H₄—C(CH₃)₂—C₆H₁₃,    —C₂H₄—CH(CH₃)—C₇H₁₅, —CH₂—C(CH₃)₂—C₇H₁₅, —CH₂—CH(CH₃)—C₁₇,    —C(CH₃)₂—C₈H₁₇, —CH(CH₃)—C₉H₁₉, —C₁₂H₂₅, —C₈H₁₆—C(CH₃)₃,    —C₉H₁₈—CH(CH₃)₂, —C₈H₁₆—CH(CH₃)—C₂H₅, —C₇H₁₄—C(CH₃)₂—C₂H₅,    —C₇H₁₄—CH(CH₃)—C₃H₇, —C₆H₁₂—C(CH₃)₂—C₃H₇, —C₆H₁₂—CH(CH₃)—C₄H₉,    —C₅H₁₀—C(CH₃)₂—C₄H₉, —C₅H₁₀—CH(CH₃)1′C₅H₁₁, —C₄H₈(CH₃)₂—C₅H₁₁,    —C₄—CH(CH₃)—C₆H₁₃, —C₃H₆—C(CH₃)₂—C₆H₁₃, —C₃H₆—CH(CH₃)—C₇H₁₅,    C₂H₄—C(CH₃)₂—C₇H₁₅, —C₂H₄—CH(CH₃)—C₈H₁₇, CH₂—C(CH₃)₂—C₈H₁₇,    —CH₂—CH(CH₃)—C₉H₁₉, —C(CH₃)₂—C₉H₁₉, —CH(CH₃)—C₁₀H₂₁;-   an alkyl group, if not stated otherwise, denotes a linear or    branched C₁-C₆-alkyl, preferably a linear or branched chain of one    to five carbon atoms, a linear or branched C₁-C₆-alkenyl or a linear    or branched C₂-C₆-alkinyl group, which can optionally be substituted    by one or more substituents R³, preferably by halogen;-   the C₁-C₆-alkyl, C₁-C₆-alkenyl and C₁-C₆-alkinyl residue may be    selected from the group comprising —CH₃, —C₂H₅, —CH═CH₂, —C≡CH,    —C₃H₇, —CH(CH₃)₂, —CH₂—CH═CH₂, —C(CH₃)—CH₂, —CH═CH—CH₃, —C≡C—CH₃,    —CH₂—C≡CH, —C₄H₉, —CH₂—CH(CH₃)₂, —CH(CH₃)—C₂H₅, —C(CH₃)₃, —C₅H₁₁,    —C₆H₁₃, —C(R³)₃, —CR³(R^(3′))R^(3″), —C₂(R³)₅, —CH(CH₃)—C₂H₅,    —C(CH₃)₃, —C₅H₁₁, —C₆H₁₃, —C(R³)₃, —CR³(R^(3′))₂,    —CR³(R^(3′))R^(3″), —C₂(R³)₅, —CH₂—C(R³)₃, —CH₂—CR³(R^(3′))₂,    —CH₂—CR³(R^(3′))R^(3″), —C₃(R³)₇, C₂H₄—C(R³)₃, —C₂H₄—CH═CH₂,    —CH═CH—C₂H₅, —CH═C(CH₃)₂, —CH₂—CH═CH—CH₃, —CH═CH—CH═CH₂, —C₂H₄—C═CH,    —C≡C—C₂h₅, —CH₂—C≡C—CH₃, —C≡C—CH—CH═CH₂, —CH═CH—C≡CH, —C≡C—C≡CH,    —C₂H₄CH(CH₃)₂, —CH(CH₃)—C₃H₇, —CH₂—CH(CH₃)—C₂H₅, —CH(CH₃)—CH(CH₃)₂,    —C(CH₃)₂—C₂H₅, —CH₂C(CH₃)₃, —C₃H₆—CH═CH₂, —CH═CH—C₃H₇,    —C₂H₄—CH═CH—CH₃, —CH₂—CH═CH—C₂H₅, —CH₂—CH═CH—CH═CH₂,    —CH═CH—CH═CH—CH₃, —CH═CH—CH₂—CH═CH₂, —C(CH₃)═CH—CH═CH₂,    —CH═C(CH₃)—CH═CH₂, —CH═CH—C(CH₃)═CH₂, —CH₂—CH═C(CH₃)₂,    —C(CH₃)═C(CH₃)₂, —C₃H₆—C≡CH, —C≡C—C₃H₇, —C₂H₄—C≡C—CH₃,    —CH₂—C≡C—C₂H₅, —CH₂—C≡C—CH═CH₂, —CH₂—CH═CH—C≡CH, —CH₂—C≡C—C≡CH,    —C≡C—CHαCH—CH₃, —CH═CH—C—C≡C—CH₃, —C≡C—C≡C—CH₃, —C≡C—CH₂—CH═CH₂,    —CH═CH—CH₂C≡CH, —C═C—CH₂—C═CH, —C(CH₃)═CH—CH═CH₂, —CH═C(CH₃)—CH′CH₂,    —CH═CH—C(CH₃)═CH₂, —C(CH₃)═CH—C≡CH, —CH═C(CH₃)—C≡CH,    —C≡C—C(CH₃)═CH₂, —C₃H₆—CH(CH₃)₂, —C₂H₄—CH(CH₃)—C₂H₅, —CH(CH₃)—C₄H₉,    —CH₂—CH(CH₃)—C₃H₇, —CH(CH₃)—CH₂—CH(CH₃)₂, —CH(CH₃)—CH(CH₃)—C₂H₅,    —CH₂—CH(CH₃)—CH(CH₃)₂, —CH₂—C(CH₃)₂—C₂H₅, —C(CH₃)₂—C₃H₇,    —C(CH₃)₂—CH(CH₃)₂, —C₂H₄—C(CH₃)₃, —CH(CH₃)—C(CH₃)₃, —C₄H₈—CH═CH₂,    —CHαCH—C₄H₉, —C₃H₆—CH═CH—CH₃, —CH₂—CH═CH—C₃H₇, —C₂H₄—CH═CH—C₂H₅,    —CH₂—C(CH₃)═C(CH₃)₂, —C₂H₄—CH═C(CH₃)₂, —C₄H₈—C≡CH, —C≡C—C₄H₉,    —C₃H₆—C≡c-CH₃, —CH₂—C≡C—C₃H₇, —C₂H₄—C≡C—C₂H₅; R³, R^(3′) or R^(3″)    being as defined above;-   a cycloalkyl group denotes a non-aromatic ring system containing    three to eight carbon atoms, preferably four to eight carbon atoms,    wherein one or more of the carbon atoms in the ring can be    substituted by a group X, X being as defined above; the    C₃-C₈-cycloalkyl residue may be selected from the group comprising    -cyclo-C₃H₅, -cyclo-C₄H₇, -cyclo-C₅H₉, -cyclo-C₆H₁₁, -cyclo-C₇H₁₃,    -cyclo-C₈H₁₅;-   an alkoxy group denotes an O-alkyl group, the alkyl group being as    defined above; the alkoxy group is preferably a methoxy, ethoxy,    isopropoxy, t-butoxy or pentoxy group,-   an haloalkyl group denotes an alkyl group which is substituted by    one to five halogen atoms, the alkyl group being as defined above;    the haloalkyl group is preferably a —C(R¹⁰)₃, —CR¹⁰(R^(10′))₂,    —CR¹⁰(R^(10′))R^(10″), —C₂(R¹⁰)₅, —CH₂—C(R¹⁰)₃, —CH₂—CR¹⁰(R^(10′))₂,    —CH₂—CR¹⁰(R^(10′))R^(10″), —C₃(R¹⁰)₇ or —C₂H₄—C(R¹⁰)₃, wherein R¹⁰,    R^(10′), R^(10″) represent F, Cl, Br or I, preferably F;-   a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group    being as defined above;-   an haloalkyloxy group denotes an alkoxy group which is substituted    by one to five halogen atoms, the alkyl group being as defined    above; the haloalkyloxy group is preferably a —OC(R¹⁰)₃,    —OCR¹⁰(R^(10′))₂, —OCR¹⁰(R^(10′))R^(10″), —OC₂(R¹⁰)₅, —OCH₂—C(R¹⁰)₃,    —OCH₂—CR¹(R^(10′))₂, —OCH₂CR¹⁰(R^(10′))R^(10″), —OC₃(R₁₀)₇ or    —OC₂H₄(R¹⁰)₃, wherein R¹⁰, R^(10′), R^(10″) represent F, Cl, Br or    I, preferably F;-   a hydroxyalkylamino group denotes an (HO-alkyl)₂-N-group or    HO-alkyl-NH-group, the alkyl group being as defined above;-   a halogen group is chlorine, bromine, fluorine or iodine;-   an aryl group preferably denotes an aromatic group having five to    fifteen carbon atoms, which can optionally be substituted by one or    more substituents R³, where R³ is as defined above; the aryl group    is preferably a phenyl group, —CH₂—C₆H₄, —C₂H₄—C₆H₄, —CH═CH—C₆H₄,    —C≡C—C₆H₄, -o-C₆H₄—R³, -m-C₆H₄—R³, -p-C₆H₄—R³, -o-CH₂—C₆H₄—R³,    -m-CH₂—C₆H₄—R³, -p-CH₂—C₆H₄—R³;-   a heteroaryl group denotes a 5- or 6-membered heterocyclic group    which contains at least one heteroatom like O, N, S. This    heterocyclic group can be fused to another ring. For example, this    group can be selected from an oxazol-2-yl, oxazol-4-yl, oxazol-5-yl,    thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl,    isothiazol-4-yl, isothiazol-5-yl, 1,2,4-oxadiazol-3-yl,    1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl,    1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl, 1,2,5-thiadiazol-3-yl,    1-imidazolyl, 2-imidazolyl, 1,2,5-thiadiazol-4-yl, 4-imidazolyl,    1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl,    3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl,    4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl,    2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, indolyl,    indolinyl, benzo-[b]-furanyl, benzo[b]thiophenyl, benzimidazolyl,    benzothiazolyl, quinazolinyl, quinoxazolinyl, or preferably    isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, quinolinyl,    tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl group.    This heterocyclic group can optionally be substituted by one or more    substituents R³, where R³ is as defined above.

However, the following compounds are excluded from Formula (XI):2-thiophenecarboxylicacid-5-bromo-2-[[(4-chlorophenyl)amino]carbonyl]hydrazide,2-thiophenecarboxylic acid-2-[[(4-ethoxyphenyl)amino]carbonyl]hydrazide,2-thiophenecarboxylicacid-3-methyl-2-[[(3,4-dichlorophenyl)amino]carbonyl]hydrazide,2-thiophenecarboxylic acid-2-[[(4-methylphenyl)amino]carbonyl]hydrazide,2-thiophene-carboxylicacid-2-[[(4-chlorophenyl)amino]carbonyl]hydrazide, 2-thiophenecarboxylicacid-2-[[(3-chlorophenyl)amino]carbonyl]hydrazide and2-thiophenecarboxylic acid-2-[(phenylamino)carbonyl]hydrazide.

Furthermore the present invention is directed to novel compounds of thegeneral Formula (XII) and pharmaceutically acceptable salts thereof:

wherein

-   R¹¹ is an optionally substituted phenyl group by one to five    substituents R⁹ or an optionally substituted C₄-C₂₀-alkyl group by    one or more substituents R³;-   R⁹ is independently of each other —F, —I, —SO₂NHR⁴, —SO₂N(R⁴)₂,    —NR⁴R⁵, —NR⁴—CO—(C₁-C₆)-haloalkyl, —NO₂, —NR₄—SO₂—(C₁-C₆)-haloalkyl,    —CN, C₂-C₅-alkyl, cycloalkyl, —OH, —SH, alkylthio methoxy, propoxy,    hydroxyalkylamino, haloalkyloxy, haloalkyl, hydroxyalkyl, aryl or    heteroaryl;-   R¹⁰ is independently of each other —H, —F, —Cl, —I, —NO₂, NR⁴R⁵,    —CN, C₂-C₅-alkyl, cycloalkyl, —OH, —SH, alkylthio,    hydroxyalkylamino, hydroxyalkyl, aryl or heteroaryl;-   wherein said C₂-C₅-alkyl group of R⁹ and R¹⁰ denotes a linear or    branched C₂-C₅-alkyl, a linear or branched C₂-C₅-alkenyl or a linear    or branched C₂-C₅-alkinyl group, which can optionally be substituted    by one or more substituents R³, preferably by halogen; the    C₂-C₅-alkyl, C₂-C₅-alkenyl and C₂-C₅-alkinyl residue may be selected    from the group comprising —C₂H₅, —CH═CH₂, —C≡CH, —C₃H₇, —CH(CH₃)₂,    —C≡C—CH₃, —CH₂—C≡CH, —CH₂—CH═CH₂, —C(CH₃)═CH₂, —CH═CH—CH₃, —C₄H₉,    —C₂—CH(CH₃)₂, —CH(CH₃)—C₂H₅, —C(CH₃)₃, —C₅H₁₁, —C(R³)₃,    —CR³(R^(3′))₂, —CR³(R^(3′))R^(3″), —C₂(R³)₅, —CH₂—C(R³)₃,    —CH₂—CR³(R^(3′))₂, —CH₂—CR³(R^(3′))R^(3″), —C₃(R³)₇, —C₂H₄—C(R³)₃,    —C₂H₄—CH═CH₂, —CH═CH—C₂H₅, —CH═C(CH₃)₂, —CH₂—CH═CH—CH₃,    —CH═CH—CH═CH₂, —C₂H₄—C≡CH, —C≡C—C₂H₅, —CH₂—C≡C—CH₃, —C≡C—CH═CH₂,    —CH═CH—C≡CH, —C≡C—C≡CH, —C₂H₄—CH(CH₃)₂, —CH(CH₃)—C₃H₇,    —CH₂—CH(CH₃)—C₂H₅, —CH(CH₃)—CH(CH₃)₂, —C(CH₃)₂—C₂H₅, —CH₂—C(CH₃)₃,    —C₃H₆—CH═CH₂, —CH═CH—C₃H₇, —C₂h₄-CH═CH—CH₃, —CH₂—CH═CH—C₂H₅,    —CH₂—CH═CH—CH═CH₂, —CH═CH—CH═CH—CH₃, —CH═CH—CH₂—CH═CH₂,    —C(CH₃)═CH—CH═CH₂, —CH═C(CH₃)—CH═CH₂, —CH═CH—C(CH₃)═CH₂,    —CH₂—CH═C(CH₃)₂, —C(CH₃)═C(CH₃)₂, —C₃H₆—C≡CH, —C≡C—C₃H₇,    —C₂H₄—C≡C—CH₃, —CH₂—C≡C—C₂H₅, —CH₂—C≡CH—C═CH₂, —CH₂—CH═CH—C≡CH,    —CH₂—C≡C—C≡CH, —C≡C—CH═CH—CH₃, —CH═CH—C≡C—CH₃, —C≡C—C≡C—CH₃,    —C≡C—CH₂—CH═CH₂, —CH═CH—CH₂—C≡CH, —C≡C—CH₂—C≡CH, —C(CH₃)═CH—CH═CH₂,    —CH═C(CH₃)—CH═CH₂, —CH═CH—C(CH₃)═CH₂, —C(CH₃)═CH—C≡CH,    —CH═C(CH₃)—C≡CH, —C≡C—C(CH₃)═CH₂;-   R³, R^(3′) or R^(3″) are defined as above for Formula (XII);-   R⁴ is defined as above for Formula (XII);-   R⁵ is defined as above for Formula (XII);-   said C₂-C₂₀-alkyl residue is defined as above for Formula (XII);-   an alkyl group, referring to R³, R^(3′), ^(3″), R⁴ R⁵R⁹ or R¹⁰    denotes a linear or branched C₁-C₆-alkyl, preferably a linear or    branched chain of one to five carbon atoms, a linear or branched    C₁-C₆-alkenyl or a linear or branched C₁-C₆-alkinyl group, which can    optionally be substituted by one or more substituents R³, preferably    by halogen; the C₁-C₆-alkyl, C₁-C₆-alkenyl and C₁-C₆alkinyl residue    may be selected from the group comprising —CH₃, —C₂H₅, —CH═CH₂,    —C≡CH, —C₃H₇, —CH(CH₃)₂, —CH₂—CH═CH₂, —C(CH₃)═CH₂, —CH═CH—CH₃,    —C≡CH₃, —CH₂—C≡CH, —C₄H₉, —CH₂—CH(CH₃)₂, —CH(CH₃)—C₂H₅, —C(CH₃)₃,    —C₅H₁₁, —C₆H₁₃, —C(R³)₃, —CR³(R^(3′))₂, —CR³(R^(3′))R^(3″),    —C₂(R³)₅, —CH₂—C(R³)₃, —CH₂—CR³(R^(3′))₂, —CH—CR³(R^(3′))R^(3″),    —C₃(R³)₇, —C₂H₄—C(R³)₃, —C₂H₄—CH═CH₂, —CH═CH—C₂H₅, —H═C(CH₃)₂,    —CH₂—CH═CH—CH₃, —CH═CH—CH═CH₂, —C₂H₄—C≡CH, —C≡C—C₂H₅, —CH₂—C≡C—CH₃,    —C≡C—CH═CH₂, —CH═CH—C≡CH, —C≡C—C≡CH, —C₂H₄—CH(CH₃)₂, —CH(CH₃)—C₃H₇,    —CH₂CH(CH₃)—C₂H₅, —CH(CH₃)—CH(CH₃)₂, —C(CH₃)₂—C₂H₅, —CH₂—C(CH₃)₃,    —C₃H₆—CH═CH₂, —CH═CH—C₃H₇, —C₂H₄—CH═CH—CH₃, —CH₂—CH═CH—C₂H₅,    —CH₂—CH═CH—CH═CH₂, —CH═CH—CH═CH—CH₃, —CH═CH—CH₂—CH═CH₂,    —C(CH₃)═CH—CH═CH₂, —CH═C(CH₃)—CH═CH, —CH═CH—C(CH₃)═CH₂,    —CH₂—CH═C(CH₃)₂, —C(CH₃)═C(CH₃)₂, —C₃H₆—C≡CH, —C≡C—C₃H₇,    —C₂H₄—C═C—CH₃, —CH₂—C≡C—C₂H₅, —CH₂—C≡CH═CH₂, —CH₂—CH═CH—C≡CH,    —CH₂—C≡C—C≡CH, —C≡C—CH═CH—CH₃, —CH═CH—C≡C—CH₃, —C≡C—CH₂—CH═CH₂,    —CH═CH—CH₂—C≡CH, —C≡C—CH₂—C≡CH, —C(CH₃)═CH—CH═CH₂,    —CH═C(CH₃)—CH═CH₂, —CH═CH—C(CH₃)═CH₂, —C(CH₃)═CH—C≡CH,    —CH═C(CH₃)—C═CH, —C≡C—C(CH₃)αCH₂, —C₃H₆—CH(CH₃)₂,    —C₂H₄—CH(CH₃)—C₂H₅, —CH(CH₃)—C₄H₉, —CH₂—CH(CH₃)—C₃H₇,    —CH(CH₃)—CH—CH(CH₃)₂, —CH(CH₃)—CH(CH₃)—C₂H₅, —CH₂—CH(CH₃)—CH(CH₃)₂,    —CH₂—C(CH₃)₂—C₂H₅, —C(CH₃)₂—C₃H₇, —C(CH₃)₂—CH₃)₂—CH(CH₃)₂,    —C₂H₄—C(CH₃)₃, —CH(CH₃)—C(CH₃)₃, —C₄H₈—CH═CH₂, —CH═CH—C₃H₉,    —C₃H₆—CH═CH—CH₃, —CH₂—CH═CH—C₃H₇, —C₂H₄—CH═CH—C₂H₅, —CH₂—C(CH₃)₂,    —C₂H₄—CH═C(CH₃)₂, —C₄H₈—C≡CH, —C≡C—C₄H₉, —C₃H₆—C≡C—CH₃,    —CH₂—C≡C—C₃H₇, —C₂H₄—C≡C—C₂H₅; R³, R^(3′) or R^(3″) being as defined    above;-   an cycloalkyl group is defined as above in Formula (XII);-   an alkoxy group is defined as above in Formula (XII);-   an haloalkyl group is defined as above in Formula (XII);-   a hydroxyalkyl group is defined as above in Formula (XII);-   an haloalkyloxy group is defined as above in Formula (XII);-   a hydroxyalkylamino group is defined as above in Formula (XII);-   a halogen group is chlorine, bromine, fluorine or iodine;-   an aryl group is defined as above in Formula (XII);-   a heteroaryl group is defined as above in Formula (XII);

Furthermore the present invention is directed to novel compounds of thegeneral Formula (XIII) and pharmaceutically acceptable salts thereof:

wherein

-   A⁷ is independently C═O, C═S, SO₂, CH—OR¹³, C═NR¹², or CH—CHOR¹³;-   A⁸ is independently C(R¹⁴)₂, O, S, or NR¹²;-   A⁹ is independently C═O, C═S, SO₂, CH—OR¹³, C═NR¹², or CH₂—CHOR¹³;-   m is 0, or 1;-   q is 0, or 1;-   r is 0, or 1;-   R¹² is independently H, CH₃, CH₂—CH₃, OCH₃, OCH₂—CH₃, OH, or SH;-   R¹³ is independently H, CH₃, or CH₂—CH₃;-   R¹⁴ is independently H, alkyl, alkoxy, OH, or SH;-   A⁵ is a optionally substituted C₃-C₁₆-alkyl group by one or more    substituents R³ or an optionally substituted heteroaryl group, which    contains at least one heteroatom like O, N, S, NR⁴, SO, SO₂, Se, and    which can optionally be substituted by one or more substituents R⁸,    R^(8′), or R⁹;-   A⁶ is an optionally substituted heteroaryl group, which contains at    least one heteroatom like O, N, S, NR⁴, SO, SO₂, Se, and which can    optionally be substituted by one or more substituents R⁸, R^(8′), or    R⁹,-   or a heterocyclic group, which contains at least one double bond,    and which may contain a heteroatom like O, N, S, NR⁴, SO, SO₂, Se,    and which can optionally be substituted by one or more substituents    R⁸, R^(8′), or R⁹,-   or one of the groups below:

-   -   or one of the groups mentioned below: wherein m=0,

-   -   or one of the groups mentioned below: wherein m and r=0,

-   wherein X′, X″, X′″, X″″ is independently H, S, O, N, NR⁴, SO, SO₂,    CH, or CH₂;-   R⁸, R^(8′), R⁹ is independently H, methyl, ethyl, t-butyl, CN,    halogen, OH, alkoxy, NR⁴R⁵, COOR⁴;-   R³ is independently H, OR⁴, SR⁴, hydroxyalkyl, hydroxyalkylamino,    cycloalkyl, halogen, haloalkyl, haloalkyloxy, NO₂, CN, SO₂NR⁴R⁵,    CO₂NR⁴R⁵, COR⁴, CO₂R⁴, SO₂R⁴, SO₃R⁴, NR⁴R⁵, alkyl, aryl or    heteroaryl;-   R⁴ is H, alkyl, cycloalkyl, aryl or heteroaryl;-   R⁵ is H, O-alkyl, O-aryl, alkyl, heteroaryl or aryl;-   said heteroaryl group of A⁵ or A⁶ may be selected from the group    comprising:

-   said C₃-C₁₆alkyl residue may be selected from the group comprising    —C₃H₇, —CH(CH₃)₂, —C₄H₉, —CH₂—CH(CH₃)₂, —CH(CH₃)—C₂H₅,    —CH₂—CH(CH₃)—CH₃, —C(CH₃)₃, —C₅H₁₁, —C₂H₄CH(CH₃)₂, —CH(CH₃)—C₃H₇,    —CH₂CH(CH₃)—C₂H₅, —CH(CH₃)—CH(CH₃)₂, —C(CH₃)₂—C₂H₅, —CH₂—C(CH₃)₃,    —C₆H₁₃, —C₃H₆—CH(CH₃)₂, —C₂H₄—CH(CH₃)—C₂H₅, —CH(CH₃)—C₄H₉,    —CH₂—CH(CH₃)—C₃H₇, —CH(CH₃)—CH₂—CH(CH₃)₂, —CH(CH₃)—CH(CH₃)—C₂H₅,    —CH₂—CH(CH₃)—CH(CH₃)₂, —CH₂—C(CH₃)₂—C(CH₃)₂—C₃H₇, —C(CH₃)₂—CH(CH₃)₂,    —C₂H₄—C(CH₃)₃, —CH(CH₃)—C(CH₃)₃, —C₇H₁₅, —C₃H₆—C(CH₃)₃,    —C₄H₈—CH(CH₃)₂, —C₃H₆—CH(CH₃)—C₂H₅, —C₂H₄—C(CH₃)₂—C₂H₅,    —C₂H₄—CH(CH₃)—C₃H₇, —CH₂—C(CH₃)₂—C₃H₇, —CH₂—CH(CH₃)—C₄H₉,    —CH(CH₃)—C₅H₁₁, —C₈H₁₇, —C₄H₈—C(CH₃)₃, —C₅H₁₀—CH(CH₃)₂,    —C₄H₈—CH(CH₃)—C₂H₅, —C₂H₆—C(CH₃)₂—C₂H₅, —C₃H₆—CH(CH₃)—C₃H₇,    —C₂H₄—C(CH₃)₂—C₃H₇, —C₂H₄—CH(CH₃)—C₄H₉, —CH₂—C(CH₃)₂—C₄H₉,    —CH₂—CH(CH₃)—C₅H₁₁, —C(CH₃)₂—C(CH₃)₂—C₅H₁₁, —CH(CH₃)—C₆H₁₃, —C₉H₁₉,    —C₅H₁₀—C(CH₃)₃, —C₆H₁₂—CH(CH₃)₂, —C₅H₁₀—CH(CH₃)—C₂H₅,    —C₄H₈—C(CH₃)₂—C₂H₅, —C₄H₈—CH(CH₃)—C₃H₇, —C₃H₆—C(CH₃)₂C₃H₇,    —C₃H₆—CH(CH₃)—C₄H₉, —C₂H₄—C(CH₃)₂—C₄H₉, —C₂H₄—CH(CH₃)—C₅H₁₁,    —CH₂—C(CH₃)₂—C₅H₁₁, —CH₂—CH(CH₃)—C₆H₁₃, —C(CH₃)₂—C₆H₁₃,    —CH(CH₃)—C₇H₁₅, —C₁₀H₂₁, —C₆H₁₂—C(CH₃)₃, —C₇H₁₄—CH(CH₃)₂,    —C₆H₁₂—CH(CH₃)—C₂H₅, —C₅H₁₀—C(CH₃)₂—C₂H₅, —C₅H₁₀—CH(CH₃)—C₃H₇,    —C₄H₈—C(CH₃)₂—C₃H₇, —C₄H₈—CH(CH₃)—C₄H₉, —C₃H₆—C(CH₃)₂—C₄H₉,    —C₃H₆CH(CH₃)—C₅H₁₁, —C₅H₁₁, —C₂H₄—C(CH₃)₂—C₅H₁₁,    —C₂H₄—CH(CH₃)—C₆H₁₃, —CH₂—C(CH₃)₂—C₆H₁₃, —CH₂—CH(CH₃)—C₇H₁₅,    —C(CH₃)₂—C₇H₁₅, —CH(CH₃)—C₈H₁₇, —C₁₁H₂₃, —C₇H₁₄—C(CH₃)₃,    —C₈H₁₆—CH(CH₃)₂, —C₇H₁₄13-CH(CH₃)—C₂H₅, —C₆H₁₂—C(CH₃)₂—C₂H₅,    —C₆H₁₂—CH(CH₃)—C₃H₇, —C₅H₁₀—C(CH₃)₂—C₃H₇, —C₅H₁₀—CH(CH₃)—C₄H₉,    —C₄H₈—C(CH₃)₂—C₄H₉, —C₄H₈—CH(CH₃)—C₅H₁₁, —C₃H₆C(CH₃)₂—C₅H₁₁,    —C₃H₆—CH(CH₃)—C₆H₁₃, —C₂H₄—C(CH₃)₂—C₆H₁₃, —C₂H₄—CH(CH₃)—C₇H₁₅,    —CH₂—C(CH₃)₂—C₇H₁₅, —CH₂—CH(CH₃)—C₈H₁₇, —C(CH₃)₂—C₈H₁₇,    —CH(CH₃)—C₉H₁₉, —C₁₂H₂₅, —C₈H₁₆—C(CH₃)₃, —C₉H₁₈—CH(CH₃)₂,    —C₈H₁₆—CH(CH₃)—C₂H₅, —C₇H₁₄—C(CH₃)₂—C₂H₅, —C₇H₁₄—CH(CH₃)—C₃H₇,    —C₆H₁₂—C(CH₃)₂—C₃H₇, —C₆H₁₂—CH(CH₃)—C₄H₉, —C₅H₁₀—C(CH₃)₂—C₄H₉,    —C₅H₁₀—CH(CH₃)—C₅H₁₁, —C₄H₈—C(CH₃)₂C₅H₁₁, —C₄H₈—CH(CH₃)—C₆H₁₃,    —C₃H₆—C(CH₃)₂—C₆H₁₃, —C₃H₆—CH(CH₃)—C₇H₁₅, C₂H₄—C(CH₃)₂—C₇H₁₅,    —C₂H₄—CH(CH₃)—C₈H₁₇, CH₂—C(CH₃)₂—C₈H₁₇, —CH₂—CH(CH₃)—C₉H₁₉,    —C(CH₃)₂—C₉H₁₉, —CH(CH₃)—C₁₀H₂₁;-   an alkyl group, if not stated otherwise, denotes a linear or    branched C₁-C₆-alkyl, preferably a linear or branched chain of one    to five carbon atoms, a linear or branched C₁-C₆-alkenyl or a linear    or branched C₁-C₆-alkinyl group, which can optionally be substituted    by one or more substituents R³, preferably by halogen;-   the C₁-C₆-alkyl, C₁-C₆-alkenyl and C₁-C₆-alkinyl residue may be    selected from the group comprising —CH₃, —C₂H₅, —CH═CH₂, —C≡CH,    —C₃H₇, —CH(CH₃)₂, —CH₂—CH═CH₂, —C(CH₃)═CH, —CH═CH—CH₃, —C≡C—CH₃,    —CH₂—C≡CH, —C₄H₉, —CH₂—CH(CH₃)₂, —CH(CH₃)—C₂H₅, —C(CH₃)₃, —C₅H₁₁,    —C₆H₁₃, —C(R³)₃, —CR³(R^(3′))₂, —CR³(R^(3′))R^(3″), —C₂(R³)₅,    —CH₂—C(R³)₃, —CH₂—CR³(R^(3′))₂, —CH₂—CR³(R^(3′))R^(3″), —C₃(R³)₇,    —C₂H₄—C(R³)₃, —C₂H₄—CH═CH₂, —CH═CH—C₂H₅, —CH═C(CH₃)₂,    —CH₂—CH═CH—CH₃, —CH═CH—CH═CH₂, —C₂H₄—C≡CH, —C≡C—C₂H₅, —CH₂—C≡C—CH₃,    —C≡C—CH═CH₂, —H═CH—C≡CH, —C≡C—C≡CH, —C₂H₄—CH(CH₃)₂, —CH(CH₃)—C₃H₇,    —CH₂—CH(CH₃)—C₂H₅, —CH(CH₃)—CH(CH₃)₂, —C(CH₃)₂—C₂H₅, —CH₂—C(CH₃)₃,    —C₃H₆—CH═CH₂, —CH═CH—C₃H₇, —C₂H₄—CH═CH—CH₃, —CH₂—CH═CH—C₂H₅,    —CH₂—H═CH—CH═CH₂, —CH═CH—CH═CH—CH₃, —CH═CH—CH₂—CH═CH₂,    —C(CH₃)═CH—CH═CH₂, —CH═C(CH₃)—CH═CH₂, —CH═CH—C(CH₃)═CH₂,    —CH₂—CH═C(CH₃)₂, —C(CH₃)═C(CH₃)₂, —C₃H₆—C≡CH, —C≡C—C₃H₇,    —C₂H₄—C≡C—CH₃, —CH₂—C≡C—C₂H₅, —CH₂—C≡C—H═CH₂, —CH₂—CH═CH—C≡CH,    —CH₂—C≡C—C≡CH, —C≡C—CH═CH—CH₃, —CH═CH—C≡C—CH₃, —C≡C—C≡C—CH₃,    —C≡C—CH₂—CH═CH₂, —CH═CH—CH₂—C≡CH, —C≡C—CH—C≡CH, —C(CH₃)═CH—CH═CH₂,    —CH═C(CH₃)—CH═CH₂, —CH═CH—C(CH₃)═CH₂, —C(CH₃)═CH—C≡CH,    —CH═C(CH₃)—C≡CH, —C≡C—C(CH₃)═CH₂, —C₃H₆—CH(CH₃)₂,    —C₂H₄—CH(CH₃)—C₂H₅, —CH(CH₃)—C₄H₉, —CH₂—CH(CH₃)—C₃H₇,    —CH(CH₃)—CH₂—CH(CH₃)₂, —CH(CH₃)—CH(CH₃)—C₂H₅, —CH₂—CH(CH₃)—CH(CH₃)₂,    —CH₂—C(CH₃)₂—C₂H₅, —C(CH₃)₂—C₃H₇, —C(CH₃)₂—CH(CH₃)₂, —C₂H₄—C(CH₃)₃,    —CH(CH₃)—C(CH₃)₃, —C₄H₈—CH═CH₂, —CH═CH—C₄H₉, —C₃H₆—CH═CH—CH₃,    —CH₂—CH═CH—C₃H₇, —C₂H₄—CH═CH—C₂H₅, —CH₂—C(CH₃)═C(CH₃)₂,    —C₂H₄—CH═C(CH₃)₂, —C₄H₈—C≡CH, —C≡C—C₄H₉, —C₃H₆—C≡C—CH₃,    —CH₂—C≡C—C₃H₇, —C₂H₄—C≡C₂H₅; R³, R^(3′) or R^(3″) being as defined    above;-   a cycloalkyl group denotes a non-aromatic ring system containing    three to eight carbon atoms, preferably four to eight carbon atoms,    wherein one or more of the carbon atoms in the ring can be    substituted by a group X, X being as defined above; the    C₃-C₈-cycloalkyl residue may be selected from the group    comprising-cyclo-C₃H₅, -cyclo-C₄H₇, -cyclo-C₅H₉, -cyclo-C₆H₁₁,    -cyclo-C₇H₁₃, -cyclo-C₈H₁₅,-   an alkoxy group denotes an O-alkyl group, the alkyl group being as    defined above; the alkoxy group is preferably a methoxy, ethoxy,    isopropoxy, t-butoxy or pentoxy group.-   an haloalkyl group denotes an alkyl group which is substituted by    one to five halogen atoms, the alkyl group being as defined above;    the haloalkyl group is preferably a —C(R¹⁰)₃, —CR¹⁰(R^(10′))₂,    —CR¹⁰(R^(10′))R^(10″), —C₂(R¹⁰)₅, —CH₂—C(R¹⁰)₃, —CH₂—CR¹⁰(R^(10′))₂,    —CH₂—CR¹⁰(R^(10′))R^(10″), —C₃(R¹⁰)₇ or —C₂H₄—C(R¹⁰)₃ wherein R¹⁰,    R^(10′), R^(10″) represent F, Cl, Br or I, preferably F;-   a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group    being as defined above;-   an haloalkyloxy group denotes an alkoxy group which is substituted    by one to five halogen atoms, the alkyl group being as defined    above; the haloalkyloxy group is preferably a —OC(R¹⁰)₃,    —OCR¹⁰(R^(10′))₂, —OCR¹⁰(R^(10′))R^(10″), —OC₂(R¹⁰)₅, —OCH₂—C(R¹⁰)₃,    —OCH₂—CR¹⁰(R^(10′))₂, —OCH₂—CR¹⁰(R^(10′))R^(10″), —OC₃(R¹⁰)₇ or    —OC₂H₄—C(R¹⁰)₃, wherein R¹⁰, R^(10′), R^(10″) represent F, Cl, Br or    I, preferably F;-   a hydroxyalkylamino group denotes an (HO-alkyl)₂-N-group or    HO-alkyl-NH-group, the alkyl group being as defined above;-   a halogen group is chlorine, bromine, fluorine or iodine;-   an aryl group preferably denotes an aromatic group having five to    fifteen carbon atoms, which can optionally be substituted by one or    more substituents R³, where R³ is as defined above; the aryl group    is preferably a phenyl group, —CH₂—C₆H₄, —C₆H₄—C₆H₄, —CH═CH—C₆H₄,    —C≡C—C₆H₄, -o-C₆H₄—R³, -m-C₆H₄—R³, -p-C₆H₄—R³, -o-CH₂—C₆H₄—R³,    -m-CH₂—C₆H₄—R³, -p-CH₂—C₆H₄—R³;-   a heteroaryl group denotes a 5- or 6-membered heterocyclic group    which contains at least one heteroatom like O, N, S. This    heterocyclic group can be fused to another ring. For example, this    group can be selected from an oxazol-2-yl, oxazol-4-yl, oxazol-5-yl,    thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl,    isothiazol-4-yl, isothiazol-5-yl, 1,2,4-oxadiazol-3-yl,    1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl,    1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl, 1,2,5-thiadiazol-3-yl,    1-imidazolyl, 2-imidazolyl, 1,2,5-thiadiazol-4-yl, 4-imidazolyl,    1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl,    3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl,    4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl,    2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, indolyl,    indolinyl, benzo-[b]-furanyl, benzo[b]thiophenyl, benzimidazolyl,    benzothiazolyl, quinazolinyl, quinoxazolinyl, or preferably    isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, quinolinyl,    tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl group.    This heterocyclic group can optionally be substituted by one or more    substituents R³, where R³ is as defined above.

The invention also provides a pharmaceutical composition comprising acompound of Formula (I), (XIII), (X), (XI) or (XII), in free form or inthe form of pharmaceutically acceptable salts and physiologicallyfunctional derivatives, together with a pharmaceutically acceptablediluent or carrier therefore.

The term “physiologically functional derivative” as used herein refersto compounds which are not pharmaceutically active themselves but whichare transformed into their pharmaceutical active form in vivo, i.e. inthe subject to which the compound is administered.

In another aspect, the present invention also provides a method for thetreatment or prophylaxis of a condition where there is an advantage ininhibiting quorum sensing which comprises the administration of aneffective amount of a compound of Formula (I), (XIII), (X), (XI) or(XII) and physiologically acceptable salts or physiologically functionalderivatives thereof. The term “quorum sensing” is intended to describecell-density dependent gene regulation through a diffusible signalmolecule (Fuqua et al., J. Bacteriol. 176:269-75, 1994).

The invention is also directed to the use of compounds of Formula (I),(XIII), (X), (XI) or (XII) and of their pharmacologically tolerablesalts or physiologically functional derivatives for the production of amedicament or medical device for the prevention and treatment ofdiseases, where quorum sensing inhibition is beneficial. Furthermore,the invention is also directed to the use of compounds of Formula (I),(XIII), (X), (XI) or (XII) and of their pharmacologically tolerablesalts or physiologically functional derivatives for the production of anantibacterial agent for the prevention and treatment of bacterialbiofilms in industrial and environmental settings.

In addition, the present invention provides methods for preparing thedesired compounds of Formula (I), (XIII), (X), (XI) or (XII).

One possibility for the synthesis of compounds of Formula (I) (m, p=0)or compounds of Formula (XI) comprises the step of reacting an amine ofFormula (II) with a compound of Formula (III). Possibilities forpreparing different amides are described by J. Zabicky in “The Chemistryof Amides”, in the serial of S. Patai (ed.), “The Chemistry ofFunctional Groups”, John Wiley & Sons, 1975, p. 74-131. Methods forpreparing thioamides are described in Houben-Weyl, J. Falbe (ed.), G.Thieme Verlag, vol. E5, p. 1219-59. Methods for preparing sulfamides aredescribed by Caldwell et al., J. Am. Chem. Soc. 1944, 66, 1479-82, or byFlynn et al, Med. Chem. Res., 1998, 8, 219-43 and Dziadulewicz et al,Bioorg. Med. Chem. Lett. 2001, 11, 5, 705-10.

One method for preparing the compounds of Formula (I) (p=0, n=1) orcompounds of Formula (X) comprises the step of reacting a compound ofFormula (IV) with a compound of Formula (III). Other methods forpreparing different 1,2-diacylhydrazines are described in Houben-Weyl,“Methoden der organischen Chemie”, Vierte Auflage, G. Thieme Verlag, J.Falbe (ed.), vol. E5, p. 1173-80 or P. A. S. Smith, “Open-Chain OrganicNitrogen Compounds”, W. A. Benjamin Inc., New York, vol. 2, p. 173-201.Methods for preparing different 1,2-disulfonylhydrazines are describedin Arch. Pharm. 1953, 286, 338-43 or in U.S. Pat. No. 6,291,504. Methodsfor preparing 1-acyl-2-sulfonylhydrazines are described in Russ. J. Gen.Chem. 2000, 70, 3, 459-60 or by Leadini et al., J. Chem. Soc. PerkinTrans. 1 1998, 1833-8 and by M. Reinecke et al., J. Org. Chem. 1988, 53,1, 208-10.

One possibility for the synthesis of compounds of Formula (I) (n,p=1) orcompounds of Formula (XII) comprises the step of reacting a compound ofFormula (V) with a compound of the Formula (VI). For example, one methodfor preparing carbamoylhydrazide is described in Bull. Soc. Chim. Fr.1975, 864.

One possibility for preparing the compounds of Formula (XIII) (A⁷,A⁹=CO, A⁸=CH₂) comprises the step of reacting a compound of Formula XIVwith a compound of the Formula XV. For example, this method is describedin Synthesis 1992, 1213-1214.

One method for preparation of compounds of Formula (XIV) comprises thestep of reacting a carboxylic acid chloride with Meldrum's acid inpresence of a base. For example, this reaction is described in Org.Synth., Coll. Vol. 7, 359-360 (Org. Synth. 1984, Ann. Vol. 63, 198-199),or J. Org. Chem. 1978, 43, 2087-2088, and Bull. Chem. Soc. Jpn. 1982,55, 2186-2189.

Another possibility for preparing compounds of Formula (XIII) (A⁷,A⁹=CO, A⁸CH₂) comprises the reaction of a 3-oxo carboxylic acid chloridewith a compound of Formula (XV). For example, this procedure isdescribed in Chem. Pharm. Bull. 1980, 28, 2494-2502.

Another possibility for preparing compounds of Formula (XIII) (A⁷,A⁹=CO, A⁸=CH₂) comprises the reaction of a 3-oxo carboxylic acid esterwith a compound of Formula (XV). For example, this procedure isdescribed in Gazz. Chim. Ital. 1936, 66, 723-731.

Another possibility for preparing the compounds of Formula (XIII) (A⁷,A⁹=CO, A⁸=CH₂) comprises the reaction of a 3-oxo carboxylic acid with orwithout 3-oxo protection with a compound of Formula (XV) using a peptidecoupling method. For example, this procedure is described in TetrahedronLett. 1996, 37, 1883-1884, and Chem. Biol. 2003, 10, 81-89.

Another possibility for preparing compounds of Formula (XIII) (A⁷,A⁹=CO, A⁸=CH₂) comprises the reaction of a deprotonated methyl ketonewith an isocyanate. For example, this method is described in J. Med.Chem. 1993, 36, 2943-2949, or J. Med. Chem. 1993, 36, 3386-3396.

Other methods for preparing compounds of Formula (XIII) are described inChem. Pharm. Bull. 1984, 32, 3848-3856, or Tetrahedron Lett. 2001,5195-5197, and J. Am. Chem. Soc. 1995, 117, 12360-12361.

One possibility for preparing the compounds of Formula (XIII) (A 7,A⁹=CO, A⁸=NR¹²) comprises the step of reacting a compound of Formula(XVI) with a compound of Formula (XVII). For example, this methoddescribed in Farmaco Ed. Sci. 1982, 37, 335-342, or in Monatsh. Chemie1981, 112, 871-874, or in Monatsh. Chemie 1982, 113, 101-110, or in J.Am. Chem. Soc. 2000, 122, 8155-8167, or in Synth. Commun. 1989, 19,3543-3552.

A preferred compound of Formula (I) is a compound wherein p, and n are0, A¹ represents a substituted monocyclic aromatic ring system, and A²represents an optionally substituted monocyclic aromatic ring system.

A preferred compound of Formula (I) is a compound wherein p, and n are0, A¹ represents a substituted monocyclic aromatic ring system, and A²represents an optionally substituted alkyl group.

A more preferred compound of Formula (I) is a compound wherein p is 0and n is 1, one of A¹ and A² represent an optionally substituted5-membered aromatic ring system, and the other one of A¹ and A²represent an optionally substituted alkyl group or a substitutedmonocyclic aromatic ring system.

A more preferred compound of Formula (I) is a compound wherein p is 0and n is 1, A¹ and A² represent an optionally substituted 5-memberedaromatic ring system.

A more preferred compound of Formula (I) is a compound wherein p, and nare 1, one of A¹ and A² represent an optionally substituted 5-memberedaromatic ring system, and the other one of A¹ and A² represent anoptionally substituted alkyl group or a substituted monocyclic aromaticring system.

A more preferred compound of Formula (I) is a compound wherein p, n are1, A¹ and A² represents an optionally substituted 5-membered aromaticring system.

A more preferred compound of Formula (I) is a compound wherein p and nare 1, one of A¹ and A² represent an optionally substituted 5-memberedaromatic ring system, and the other one of A¹ and A² represent anoptionally substituted alkyl group or a substituted monocyclic aromaticring system.

A more preferred compound of Formula (I) is a compound wherein p and nare 1 A¹ and A² represent an optionally substituted 5-membered aromaticring system.

In the compounds of Formula (I), R is independently H, alkyl,cycloalkyl, aryl or heteroaryl. Preferably, R is H.

In the compounds of Formula (I), R¹ is independently H, alkyl,cycloalkyl, aryl or heteroaryl. Preferably, R¹ is H.

In the compounds of Formula (I), R² is independently H, alkyl,cycloalkyl, aryl or heteroaryl. Preferably, R² is H.

Preferably, R³ in Formula (XIII), (I), (X), (XI) or (XII) isindependently H, halogen, CF₃, OCF₃, phenyl or alkyl.

R⁴ in Formula (XIII), (I), (X) or (XII) is independently H, alkyl,cycloalkyl, aryl or heteroaryl. Preferably R⁴ is H.

R⁵ in Formula (XIII), (I), (X) or (XII) is independently H, O-alkyl,O-aryl, alkyl, heteroaryl or aryl. Preferably R⁵ is H.

In Formula (I) Y¹ and Y² are independently from each other CO, CS, SO₂,or CNR⁵, preferably both are CO.

In Formula (I) Z is independently S, O, N, NR⁴, CO, CO₂, CS, SO or SO₂.Preferably, Z is O, CO, CO₂.

In Formula (I) or (X) X is independently S, O, N, NR⁴, SO or SO₂.Preferably, X is N, S, O, NR⁴.

In Formula (I), most preferably, n is 1 and p is 0.

In Formula (I), more preferably, n and p are 0.

In Formula (I), most preferably, n and p are 1.

In Formula (XII), most preferably q is 1 or 2.

A preferred compound of Formula (XIII) is a compound wherein R¹⁴ is H ormethyl more preferably H.

A preferred compound of Formula (XIII) is a compound wherein R¹² is H ormethyl more preferably H.

A preferred compound of Formula (XIII) is a compound wherein A⁸ is CH₂.

A preferred compound of Formula (XIII) is a compound wherein A⁷ and/orA) are CO.

A preferred compound of Formula (XIII) is a compound wherein A⁵ isC₆-C₁₀-alkyl.

A preferred compound of Formula (XIII) is a compound wherein A⁶ isselected from the following group:

A preferred compound of Formula (XIII) is a compound wherein A⁶ is5-membered ring system wherein X′ is N, and X″ is O or S, and X′″ is CHor CH₂.

A preferred compound of Formula (XIII) is a compound wherein A⁶ is5-membered ring system wherein X′ is N and X″ is N, and X′″ is CH orCH₂.

A preferred compound of Formula (XIII) is a compound wherein A⁶ is6-membered ring system wherein X′ is N, and X″ is O or S, and X′″ is CHor CH₂, and X″″ is CH or CH₂.

A preferred compound of Formula (XIII) is a compound wherein A⁶ is6-membered ring system wherein X′ is N and X″ is N, and X′″ is CH orCH₂, and X″″ is CH or CH₂.

A preferred compound of Formula (XIII) is a compound wherein m is 1 andq, r are 0.

A preferred compound of Formula (XIII) is a compound wherein R¹³ is R.

A preferred compound of Formula (XIII) is a compound wherein R⁶, R^(8′)or R⁹ are H.

Most preferred is the use of one or more compounds of Formula (I), (X),(XI) or (XII), including the compounds excluded by any of thedisclaimers, and/or pharmaceutically acceptable salts thereof forregulation of the quorum sensing system of microorganisms, in particulargram-negative bacteria. In one embodiment of the invention also the useof the following compounds is preferred:

-   2-Chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid    (2-methyl-2H-pyrazol-3-yl)-amide    2,5-Dichloro-thio-phene-3-carboxylic acid pyridin-3-ylamide;    2-[(2-Chloro-4-trifluoro-methyl-pyrimidine-5-carbonyl)-amino]-thiophene-3-carboxylic    acid methyl ester;    2-Chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid    (3-trifluoromethyl-phenyl)-amide;    2-Chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid    (4-trifluoromethoxy-phenyl)-amide;    2-Methyl-6-trifluoromethyl-nicotinic acid    N′-(thiophene-2-carbonyl)-hydrazide; 4-Trifluoromethyl-benzoic acid    N′-(4-methyl-thiophene-2-carbonyl)-hydrazide; 4-Chloro-benzoic acid    N′-(4-methoxy-thiophene-3-carbonyl)-hydrazide; 3-Chloro-benzoic acid    N′-(thiophene-2-carbonyl)-hydrazide;    N′-(3-Methyl-1,4-dioxy-quinoxaline-2-carbonyl)-thiophene-2-carboxylic    acid hydrazide; Furan-2-carboxylic acid    N′-(thiophene-2-carbonyl)-hydrazide; Furan-2-carboxylic acid    N′-(3-chloro-4-methyl-thiophene-2-carbonyl)-hydrazide;    Furan-2-carboxylic acid    N′-(3-ethoxy-thiophene-2-carbonyl)-hydrazide; Furan-2-carboxylic    acid N′-(3-chloro-benzo[b]thiophene-2-carbonyl)-hydrazide;    Thiophene-2-carboxylic acid    N′-(5-bromo-4-methoxy-thiophene-3-carbonyl)-hydrazide;    Thiophene-2-carboxylic acid    N′-(3-chloro-4-methyl-thiophene-2-carbonyl)-hydrazide;    Thiophene-2-carboxylic acid N′-(thiophene-2-carbonyl)-hydrazide;    3-Chloro-thiophene-2-carboxylic acid    N′-(thiophene-2-carbonyl)-hydrazide; Thiophene-2-carboxylic acid    N′-(5-bromo-thiophene-2-carbonyl)-hydrazide;    3-Chloro-benzo[b]thiophene-2-carboxylic acid    N′-(thiophene-2-carbonyl)-hydrazide; Thiophene-2-carboxylic acid    N′-(4-bromo-1,5-dimethyl-1H-pyrazole-3-carbonyl)-hydrazide;    Thiophene-2-carboxylic acid N′-butyryl-hydrazide.

Preferred compounds of the present invention and/or pharmaceuticallyacceptable salts thereof are selected from the group comprising;

-   3-Oxo-nonanoic acid (2H-pyrazol-3-yl)-amide; 3-Oxo-nonanoic acid    (2-methyl-2H-pyrazol-3-yl)-amide; 3-Oxo-dodecanoic acid    (2-methyl-2H-pyrazol-3-yl)-amide; 3-Oxo-nonanoic acid    (2-ethyl-2H-pyrazol-3-yl)-amide; 3-Oxo-dodecanoic acid    (2-ethyl-2H-pyrazol-3-yl)-amide; 3-Oxo-nonanoic acid    (2,5-dimethyl-2H-pyrazol-3-yl)-amide; 3-Oxo-dodecanoic acid    (2,5-dimethyl-2H-pyrazol-3-yl)-amide; 3-Oxo-nonanoic acid    pyrazol-1-ylamide; 2-(3-Oxo-nonanoylamino)-thiophene-3-carboxylic    acid methyl ester; Z(3-Oxo-dodecanoylamino)-thiophene-3-carboxylic    acid methyl ester;    4-Methyl-2-(3-oxo-nonanoylamino)-thiophene-3-carboxylic acid ethyl    ester; 4-Methyl-2-(3-oxo-dodecanoylamino)-thiophene-3-carboxylic    acid ethyl ester; 3-Oxo-nonanoic acid    (3-methyl-isothiazol-5-yl)-amide; 3-Oxo-dodecanoic acid    (3-methyl-isothiazol-5-yl)-amide; 3-Oxo-nonanoic acid    thiazol-2-ylamide; 3-Oxo-dodecanoic acid thiazol-2-ylamide;    3-Oxo-nonanoic acid (5-acetyl-2-methylsulfanyl-thiazol-4-yl)-amide;    3-Oxo-nonanoic acid isoxazol-3-ylamide; 3-Oxo-dodecanoic acid    isoxazol-3-ylamide; 3-Oxo-nonanoic acid    (3-methyl-isoxazol-5-yl)-amide; 3-Oxo-dodecanoic acid    (3-methyl-isoxazol-5-yl)-amide; 3-Oxo-nonanoic acid    (4-methyl-oxazol-2-yl)-amide; 3-Oxo-nonanoic acid    (4cyano-2-methyl-oxazol-5-yl)-amide; 3-Oxo-nonanoic acid    (3-cyano-4,5-dimethyl-furan-2-yl)-amide; 3-Oxododecanoic acid    (3-cyano-4,5-dimethyl-furan-2-yl)-amide;    5-(3-Oxo-nonanoylamino)-furan-2-carboxylic acid methyl ester-   3-Bromo-thiophene-2-carboxylic acid (6-methoxy-pyridin-3-yl)-amide;    4-Methyl-3-[(thio-phene-2-carbonyl)-amino]-thiophene-2-carboxylic    acid methyl ester;    N-(6-Methoxy-pyridin-3-yl)-2-methylsulfanyl-nicotinamide;    5-Bromo-N-(6-methoxy-pyridin-3-yl)-nicotinamide;    N-(5-Bromo-pyridin-2-yl)-2,6-dichloro-isonicotinamide;    2-Chloro-6-methyl-N-pyridin-3-yl-iso-nicotinamide;    4-Bromo-2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid    (2-methyl-2H-pyrazol-3-yl)-amide;    2-tert-Butyl-5-methyl-2H-pyrazole-3-carboxylic acid    (2-methyl-2H-pyrazol-3-yl)-amide; Thiophene-2-carboxylic acid    [5-(4-chloro-phenyl)-2-methyl-2H-pyrazol-3-yl]-amide;    3-Chloro-N-(2-methyl-5-thiophen-2-yl-2H-pyrazol-3-yl)-benzamide;    6-Bromo-hexanoic acid    [5-(4chloro-phenyl)-2-methyl-2H-pyrazol-3-yl]-amide; Heptanoic acid    (2-methyl-5-phenyl-2H-pyrazol-3-yl)-amide; 6-Bromo-hexanoic acid    (2-methyl-5-phenyl-2H-pyrazol-3-yl)-amide; Heptanoic acid    (2-methyl-5-thiophen-2-yl-2H-pyrazol-3-yl)-amide; 6-Bromo-hexanoic    acid (2-methyl-5-thiophen-2-yl-2H-pyrazol-3-yl)-amide; Heptanoic    acid (4-bromo-2-methyl-2H-pyrazol-3-yl-amide; 6-Bromo-hexanoic acid    (2-methyl-2H-pyrazole-3-yl)-amide; 6-Bromo-hexanoic acid    (4-bromo-2-methyl-2H-pyrazol-3-yl)-amide; Heptanoic acid    (2-methyl-2H-pyrazol-3-yl)-amide; Thiophene-2carboxylic acid    N′-(4-trifluoromethyl-pyrimidin-2-yl)-hydrazide;    2,5-Dimethyl-2H-pyrazole-3-carboxylic acid    N′-(4-trifluoromethyl-pyrimidin-2-yl)-hydrazide;    4-Trifluoromethoxy-benzoic acid N′-(thiophene-2-carbonyl)-hydrazide;    3-Chloro-thiophene-2-carboxylic acid    N′-(1-phenyl-5-trifluoromethyl-1H-pyrazole-4-carbonyl)-hydrazide;    Thio-phene-2-carboxylic acid    N′-[1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-hydrazide;    Furan-2-carboxylic acid    N′-(5-chloro-4-methoxy-thiophene-3-carbonyl)-hydrazide;    Furan-2-carboxylic acid N′-(3-bromo-thiophene-2-carbonyl)-hydrazide;    Furan-2-carboxylic acid    N′-(2,5-dichloro-thiophene-3-carbonyl)-hydrazide;    3-Chloro-thiophene-2-carboxylic acid    N′-(3-ethoxy-thiophene-2-carbonyl)-hydrazide; Thiophene-2-carboxylic    acid N′-(3-ethoxy-thiophene-2-carbonyl)-hydrazide;    Thiophene-3-carboxylic acid N′-(thiophene-2-carbonyl)-hydrazide;    3-Bromo-thiophene-2-carboxylic acid    N′-(2-chloromethylsulfanyl-acetyl)-hydrazide;    3-Chloro-thiophene-2-carboxylic acid    N′-(3-chloro-thiophene-2-carbonyl)-hydrazide;    5-Chloro-4-methoxy-thiophene-3-carboxylic acid    N′-(thiophene-2-carbonyl)-hydrazide; Thiophene-2-carboxylic acid    N′-(5-chloro-thiophene-2-carbonyl)-hydrazide;    5-Bromo-4-methoxy-thiophene-3-carboxylic acid    N′-(5-methyl-thiophene-2-carbonyl)-hydrazide; Thiophene-2-carboxylic    acid N′-(5-methyl-thiophene-2-carbonyl)-hydrazide;    Thiophene-2-carboxylic acid    N′-(3-bromo-thiophene-2-carbonyl)-hydrazide;    3-Bromo-thiophene-2-carboxylic acid    N′-(3-ethoxy-thiophene-2-carbonyl)-hydrazide;    3-Bromo-thiophene-2-carboxylic acid    N′-(5-methyl-thiophene-2-carbonyl)-hydrazide;    3-Chloro-thiophene-2-carboxylic acid    N′-(5-chloro-thiophene-2-carbonyl)-hydrazide;    3-Chloro-benzo[b]thiophene-2-carboxylic acid    N′-(3-bromo-thiophene-2-carbonyl)-hydrazide;    3-Chloro-benzo[b]thiophene-2-carboxylic acid    N′-(5-bromo-thiophene-2-carbonyl)-hydrazide;    4-Chloro-1,3-dimethyl-1H-pyrazolo[3,4-b]-pyridine-5-carboxylic acid    N′-(thiophene-2-carbonyl-hydrazide;    2,5-Dimethyl-2H-pyrazole-3-carboxylic acid    N′-(3-chloro-benzo[b]thiophene-2-carbonyl)-hydrazide;    2,5-Dimethyl-2H-pyrazole-3-carboxylic acid    N′-(thiophene-2-carbonyl)-hydrazide;    4-Bromo-2ethyl-5-methyl-2H-pyrazole-3-carboxylic acid    N′-(5-chloro-thiophene-2-carbonyl)-hydrazide; Thiophene-2-carboxylic    acid N′-(2-tert-butyl-5-methyl-2H-pyrazole-3-carbonyl)-hydrazide;    5-tert-Butyl-2-methyl-2H-pyrazole-3-carboxylic acid    N′-(5-chloro-thiophene-2-carbonyl)-hydrazide; Thiophene-2-carboxylic    acid N′-(5-tert-butyl-2-methyl-2H-pyrazole-3-carbonyl)-hydrazide;    4Bromo-2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid    N′-(5-bromo-thiophene-2-carbonyl)-hydrazide;    4-Bromo-2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid    N′-(3-chloro-4-methylthiophene-2-carbonyl)-hydrazide;    4-Bromo-2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid    N′-(5-chloro-thiophene-2-carbonyl)-hydrazide;    4-Bromo-2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid    N′-(4,5-di-bromo-thiophene-2-carbonyl)-hydrazide;    5-Methyl-thiophene-2-carboxylic acid N′-butyryl-hydrazide;    5-Bromo-thiophene-2-carboxylic acid N′-butyryl-hydrazide;    Thiophene-2-carboxylic acid N′-(6-bromo-hexanoyl)-hydrazide;    Thiophene-2-carboxylic acid N′-heptanoyl-hydrazide;    3-Chloro-4-methyl-thiophene-2-carboxylic acid    N′-(6-bromo-hexanoyl)-hydrazide;    3-Chloro-4-methyl-thiophene-Z-carboxylic acid    N′-heptanoyl-hydrazide; 5-Methyl-thiophene-2-carboxylic acid    N′-(6-bromohexanoyl)-hydrazide; 5-Methyl-thiophene-2-carboxylic acid    N′-heptanoyl-hydrazide; 5-Bromo-thiophene-2-carboxylic acid    N′-heptanoyl-hydrazide; 3-Bromo-thiophene-2carboxylic acid    N′-octanoyl-hydrazide; Thiophene-2-carboxylic acid    N′-dodecanoyl-hydrazide; 5-Methyl-thiophene-2-carboxylic acid    N′-(3-cyclopentyl-propionyl)-hydrazide;    5-[N′-(5-Methyl-thiophene-2-carbonyl)-hydrazinol-5-oxo-pentanoic    acid methyl ester; Furan-2-carboxylic acid N′-heptanoyl-hydrazide;    Furan-2-carboxylic acid N′-(3-cyclopentyl-propionyl)-hydrazide;    3,5-Dimethyl-isoxazole-4carboxylic acid N′-octanoyl-hydrazide;    4-Bromo-2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid    N′-octanoyl-hydrazide; 2-Chloro-isonicotinic acid    N′-octanoyl-hydrazide; 2-Chloro-nicotinic acid    N′-octanoyl-hydrazide;    3-[N′-(3-Bromo-thiophene-2-carbonyl)-hydrazinol-3-oxo-propionic acid    ethyl ester;    3-[N′-(Benzo[b]thiophene-2-carbonyl)-hydrazino]-3-oxo-propionic acid    ethyl ester;    N′-(5-Chloro-thiophen-2-sulfonyl)-thiophene-2-carboxylic acid    hydrazide; Butyric acid N′-(5-chloro-thiophen-2-sulfonyl)-hydrazide;    N′-(5-Chloro-thiophen-2-sulfonyl)-heptanoic acid hydrazide;    4-Butyl-1-(thiophene-2-carbonyl)-thiosemicarbazide;    1-(4,5-Dibromo-thiophene-2-carbonyl)-4-pentyl-semicarbazide;    1-(5-Bromo-thiophene-2-carbonyl)-4-(4-fluoro-2-trifluoromethyl-phenyl)-semicarbazide;    4-(4-Chloro-3-trifluoromethyl-phenyl)-1-(4,5-dibromo-thiophene-2-carbonyl)-semicarbazide;    1-(4,5-Dibromo-thiophene-2-carbonyl)-4-(3-trifluoromethyl-phenyl)-semi-carbazide;    1-(3-Chloro-4-methyl-thiophene-2-carbonyl)-4-(4-methylsulfanyl-phenyl)-semicarbazide;    4-(4-Bromo-phenyl)-1-(3-chloro-4-methyl-thiophene-2-carbonyl)-semicarbazide;    1-(5-Bromo-thiophene2-carbonyl)-4-(2-chloromethyl-phenyl)-semicarbazide;    4(2-Chloro-methyl-phenyl)-1-(5-chloro-thiophene-2-carbonyl)-semicarbazide;    1-(5-Bromo-thiophene-2-carbonyl)-4-(4-methoxy-phenyl)-semicarbazide;    1-(5-Bromo-thiophene-2-carbonyl)-4-(2,6-difluoro-phenyl)-semicarbazide;    1-(3-Chloro-benzo[b]thiophene-2-carbonyl)-4-(2,6-dichloro-pyridinyl)-semicarbazide;    1-(3-Chloro-benzo[b]thiophene-2-carbonyl)-4-o-tolyl-semi-carbazide

The compounds of the Formula (XIII), (I), (X), (XI) or (XII) accordingto the invention can be also used in form of the corresponding saltswith inorganic or organic acids or bases. Examples of such salts are,e.g., alkali metal salts, in particular sodium and potassium salts,hydrochloride or ammonium salts.

In general, the compounds of the present invention can be used toinhibit quorum sensing signaling of bacteria employing HSLs as signalmolecules for cell-cell communication. Preferably, the compounds can beapplied to the bacteria listed in Table 1, and more preferably to thebacteria of Table 1 that are pathogens. In the following it is explainedthat the compounds of the present invention can be used as antibacterialagents in various applications.

In a preferred form, the compounds of Formula (XIII), (I), (X), (XI) or(XII) are useful for the treatment of a variety of human, animal andplant diseases, where bacterial pathogens regulate the expression ofvirulence genes and other phenotypes, e.g. biofilm formation, through anHSL-based quorum sensing system. Furthermore, as the list of organisms(see Table 1) employing quorum sensing signaling for their virulencecontinues to increase, the compounds of the invention can be used alsofor organisms which will be added to the above listed in future.

In a first embodiment, the compounds are useful for the treatment ofmammalian in particular human diseases caused by bacteria through theinhibition of the bacterial quorum sensing cascade rendering thepathogen avirulent. Such diseases include endocarditis, respiratory andpulmonary infections (preferably in immunocompromised and cysticfibrosis patients), bacteremia, central nervous system infections, earinfections including external otitis, eye infections, bone and jointinfections, urinary tract infections, gastrointestinal infections andskin and soft tissue infections including wound infections, pyoderma anddermatitis which all can be triggered by Pseudomonas aeruginosa.Furthermore, the compounds can be used for the treatment of pulmonaryinfections caused by Burkholderia cepacia (preferably inimmunocompromised and cystic fibrosis patients), gastroenteritis andwound infections caused by Aeromonas hydrophila, sepsis in tropical andsubtropical areas caused by Chromobacterium violaceum, diarrhoea withblood and haemolytic uremic syndrome (HUS) caused by Escherichia coli,yersiniosis triggered by Yersinia enterocolitica and Y.pseudotuberculosis, and transfusion-related sepsis and fistulouspyoderma caused by Serratia liquefaciens.

In a second embodiment the compounds can be used in the treatment ofimmunological diseases, particularly autoimmune diseases such aspsoriasis, rheumatoid arthritis, multiple sclerosis and type 1(autoimmune) diabetes, of cardiovascular diseases such as cardiactachyarrhythmias, ischaemic heart disease, congestive heart failure, ofallergic diseases and of diseases including cancer, breast cancer,obesity, lipid metabolism disorders, immune disease, immune deficiencyor immune disorders.

In a third embodiment, the compounds can be used to prevent and/or treatplant diseases, where inhibition of the HSL-mediated signaling systemreduces or abolishes virulence of bacterial plant pathogens. Suchdiseases include crown gall tumors caused by Agrobacterium tumefaciens,soft rot caused by Burkholderia cepacia, Erwinia carotovora and Erwiniachrysanthemi, sweet corn and maize infections caused by Pantoeastewartii and wilt disease caused by Ralstonia solanacearum.

In a fourth embodiment, the compounds can be used for the preventionand/or treatment of animal diseases, preferably fish diseases such assepticemia caused by Aeromonas hydrophila and Vibrio anguillarum,furunculosis in salmonids caused by Aeromonas salmonicida, prawninfections caused by Vibrio harveyi and enteric redmouth disease causedby Yersinia ruckeri, but also for the prevention and/or treatment ofinsect diseases caused, for example, by Xenorhabdus nematophilus.

In general, the present invention provides a method for reducing thevirulence of bacterial pathogens employing an HSL-based signalingsystem. In a preferred form, a method is provided to remove, diminish,detach or disperse a bacterial biofilm from a living or nonlivingsurface by treating the surface with a compound of Formula (XIII), (I),(X), (XI) or (XII). This method is also useful to prevent biofilmformation on a living or nonliving surface by treating the surface witha compound of Formula (XIII), (I), (X), (XI) or (XII) before bacterialcolonization can initialize. The term “biofilm” refers to cellaggregations comprising either a single type of organism or a mixture ofmore than one organism, then also referred to as “mixed biofilms”. It isclear to persons skilled in the art, that the compounds of the presentinvention can be applied in a wide variety of different fields such asenvironmental, industrial and medical applications in order to preventand/or treat damages or diseases caused by bacteria.

In one aspect, the compounds of Formula (XIII), (I), (X), (XI) or (XII)can be used for all kinds of surfaces in private and public areas, whereit is beneficial to inhibit quorum sensing systems of Gram-negativebacteria in order to prevent and/or treat colonization and biofilmformation. The compounds here can be used in form of a solution, powderor as a coating. The compound is preferably applied to the surface as asolution of the compound, alone or together with other materials such asconventional surfactants, preferably sodium dodecyl sulfate, ordetergents, biocides, fungicides, antibiotics, pH regulators, perfumes,dyes or colorants, In combination with a bacteriocidal agent, e.g., thecompounds of Formula (XIII), (I), (X), (XI) or (XII) inhibit virulenceor biofilm formation whilst the bacteriocidal agent kills the pathogens.

In one embodiment, the compounds can be used as antibacterial agent fortopical use in cleaning and treatment solutions such as disinfectants,detergents, household cleaner and washing powder formulations in theform of a spray or a dispensable liquid. In a preferred form, thesesolutions can be applied to windows, floors, clothes, kitchen andbathroom surfaces and other surfaces in the area of food preparation andpersonal hygiene. In addition, the compounds of Formula (XIII), (I),(X), (XI) or (XII) can be used as antibacterial ingredients in personalhygiene articles, toiletries and cosmetics such as dentifrices,mouthwashes, soaps, shampoos, shower gels, ointments, creams, lotions,deodorants and disinfectants and storage solutions for contact lenses.In the case of contact lenses the compounds of Formula (XIII), (I), (X),(XI) or (XII) can also be applied as coating or additive to the lensmaterial.

In another embodiment, the compounds can be used to prevent or treatbacterial biofilms in industrial settings such as ship hulls, paper andmetal manufacturing, oil recovery, food processing and otherapplications where process disturbances are referred to biofouling onsurfaces. The compounds here can be used in form of a solution, paint orcoating, for example as an ingredient in cooling lubricants. Thecompounds can also be applied to water processing plants or drinkingwater distribution systems where the colonized surface (preferably byPseudomonas aeruginosa) is preferably the inside of an aqueous liquidsystem such as water pipes, water injection jets, heat exchangers andcooling towers. Until now biocides are the preferred tools to encounterthese problems, but since biocides do not have a high specificity forbacteria, they are often toxic to humans as well. This can becircumvented by the application of the compounds of the presentinvention.

In a further embodiment, the present invention relates to a method ofinhibiting and/or preventing medical device-associated bacterialinfections. The invention provides articles coated and/or impregnatedwith a compound of Formula (XIII), (I), (X), (XI) or (XII) in order toinhibit and/or prevent biofilm formation thereon. The articles arepreferably surgical instruments, blood bag systems or medical devices;more preferably either permanently implanted devices such as artificialheart valve, prostethic joint, voice prosthesis, stent, shunt or notpermanently implanted devices such as endotracheal or gastrointestinaltube, pacemaker, surgical pin or indwelling catheter.

In a more preferred form, the indwelling catheters are urinarycatheters, vascular catheters, peritoneal dialysis catheter, centralvenous catheters and needleless connectors. The catheter materials canbe polyvinylchloride, polyethylene, latex, teflon or similar polymericmaterials, but preferably polyurethane and silicone or a mixturethereof. In order to reduce the risk of catheter-related bacterialinfections, several catheters coated and/or impregnated with antisepticor antimicrobial agents such as chlorhexidine/silver-sulfadiazine andminocycline/rifampin, respectively, have been developed. Furthermore,collection bags or layers sandwiched between an external surface sheathand a luminal silicone sheath have been constructed to overcome rapidloss of antimicrobial activity. Nevertheless, the emerging risk ofbacterial resistance against traditional antibiotics limits the routineuse of antibiotic-coated catheters.

the compounds of the present invention, however, offer the possibilityto effectively reduce catheter-related bacterial infections with a lowrisk of resistance development due to a novel therapeutic strategytargeting highly sensitive signal transduction mechanisms in bacteria.The preferred form of application is the coating and/or impregnating ofcatheter materials on both the inner and outer catheter surfaces. Morepreferably, the compounds of Formula (XIII), (I) can be included in amixture of antibacterial agents released continuously from acatheter-associated depot into the environment.

In a further embodiment, the compounds of the present invention andtheir pharmacologically acceptable salts can be administered directly toanimals, preferably to mammals, and in particular to humans asantibiotics per se, as mixtures with one another or in the form ofpharmaceutical preparations which allow enteral or parenteral use andwhich as active constituent contain an effective dose of at least onecompound of the Formula (XIII), (I), (X), (XI) or (XII) or a saltthereof, in addition to customary pharmaceutical excipients andadditives. The compounds of Formula (XIII), (I), (X), (XI) or (XII) canalso be administered in form of their salts, which are obtainable byreacting the respective compounds with physiologically acceptable acidsand bases.

The therapeutics can be administered orally, e.g., in the form of pills,tablets, coated tablets, sugar coated tablets, lozenges, hard and softgelatin capsules, solutions, syrups, emulsions or suspensions or asaerosol mixtures. Administration, however, can also be carried outrectally, e.g., in the form of suppositories, or parenterally, e.g., inthe form of injections or infusions, or percutaneously, e.g., in theform of ointments, creams or tinctures.

In addition to the active compounds of Formula (XIII), (I), (X), (XI) or(XII), the pharmaceutical composition can contain further customary,usually inert carrier materials or excipients. Thus, the pharmaceuticalpreparations can also contain additives or adjuvants commonly used ingalenic formulations, such as, e.g., fillers, extenders, disintegrants,binders, glidants, wetting agents, stabilizers, emulsifiers,preservatives, sweetening agents, colorants, flavorings or aromatizers,buffer substances, and furthermore solvents or solubilizers or agentsfor achieving a depot effect, as well as salts for modifying the osmoticpressure, coating agents or antioxidants. They can also contain two ormore compounds of the Formula (I) or (XIII) or their pharmacologicallyacceptable salts and also other therapeutically active substances.

Thus, the compounds of the present invention can be used alone, incombination with other compounds of this invention or in combinationwith other active compounds, for example with active ingredients alreadyknown for the treatment of the afore mentioned diseases, whereby in thelatter case a favorable additive effect is noticed. Suitable amounts tobe administered to mammalian in particular humans range from 5 to 1000mg,

To prepare the pharmaceutical preparations, pharmaceutically inertinorganic or organic excipients can be used. To prepare pills, tablets,coated tablets and hard gelatin capsules, e.g., lactose, corn starch orderivatives thereof, talc, stearic acid or its salts, etc. can be used.Excipients for soft gelatin capsules and suppositories are, e.g., fats,waxes, semi-solid and liquid polyols, natural or hardened oils etc.Suitable excipients for the production of solutions and syrups are,e.g., water, alcohol, sucrose, invert sugar, glucose, polyols etc.Suitable excipients for the production of injection solutions are, e.g.,water, alcohol, glycerol, polyols or vegetable oils.

The dose can vary within wide limits and is to be suited to theindividual conditions in each individual case. For the above uses theappropriate dosage will vary depending on the mode of administration,the particular condition to be treated and the effect desired. Ingeneral, however, satisfactory results are achieved at dosage rates ofabout 0.1 to 100 mg/kg animal body weight preferably 1 to 50 mg/kg.Suitable dosage fates for larger mammals, e.g., humans, are of the orderof from about 10 mg to 3 g/day, conveniently administered once, individed doses 2 to 4 times a day, or in sustained release form.

In general, a daily dose of approximately 0.1 mg to 5000 mg, preferably10 to 500 mg, per mammalian in particular human individual isappropriate in the case of the oral administration which is thepreferred form of administration according to the invention. In the caseof other administration forms too, the daily dose is in similar ranges.The compounds of Formula (I) or (XIII) can also be used in the form of aprecursor (prodrug) or a suitably modified form, that releases theactive compound in vivo.

In a further embodiment, the compounds of the present invention can beused as pharmacologically active components or ingredients of medicaldevices, instruments and articles with an effective dose of at least onecompound of the Formula (XIII), (I), (X), (XI) or (XII) or a saltthereof. The amount of the compounds used to coat for example medicaldevice surfaces varies to some extent with the coating method and theapplication field. In general, however, the concentration range fromabout 0.01 mg per cm² to about 100 mg per cm². In a similar way theamount of the compounds has to be adjusted to the application mode itthe compounds of the invention are used as components or ingredients incleaning or treatment solutions. In general, effective dosages rangefrom about 0.1 μM to about 1000 mM.

The following section shows examples for the synthesis of the compoundsof the present invention and demonstrate their quorum sensing inhibitingeffect.

EXAMPLES 1. Synthesis of Compounds of Formula (XIII), (I), (X), or (XII)

Synthesis Method A (1,2-diacylhydrazine or 1-acyl-2sulfonylhydrazineDerivatives) A solution of (1.2 eq) acid chloride or (1.2 eq) sulfonylchloride in tetrahydrofuran was added to a solution of (1 eq) hydrazidein tetrahydrofuran and molecular sieve (0.4 nm) at 0° C. The mixture wasstirred at room temperature. After 1 h the reaction mixture wasconcentrated in vacuum, and the resulting solid was purified bypreparative thin layer chromatography (Merck, 20×20 cm, Silica gel 60F₂₅₄, 1 mm) (CH₂Cl₂:MeOH, 100:1).

Synthesis Method B 1,2-diacylhydrazine or 1-acyl-2-sulfonylhydrazineDerivatives

A solution of (1.2 eq) acid chloride or (1.2 eq) sulfonyl chloride indimethylformamide was added to a solution of (1 eq) hydrazide indimethylformamide and (1.2 eq) triethylamine at 0° C. The mixture wasstirred at room temperature. After 1 h the reaction mixture wasconcentrated in vacuum, and the resulting solid was purified bypreparative thin layer chromatography (Merck, 20×20 cm, Silica gel 60F₂₅₄, 1 mm) (CH₂Cl₂:MeOH, 100:1).

Synthesis Method C 1,2diacylhydrazine or 1-acyl-2-sulfonylhydrazineDerivatives

A solution of (1.2 eq) acid chloride or (1.2 eq) sulfonyl chloride indichloromethane was added to a solution of (1 eq) hydrazide indichloromethane and (1.2 eq) triethylamine at 0° C. The mixture wasstirred at room temperature. After 1 h the reaction mixture wasconcentrated in vacuum, and the resulting solid was purified bypreparative thin layer chromatography (Merck, 20×20 cm, Silica gel 60F₂₅₄, 1 mm) (n-hexane:EtOAc, 9:1).

Synthesis Method D Amide Derivatives

A solution of (1.2 eq) acid chloride in tetrahydrofuran was added to asolution of (1 eq) amine in tetrahydrofuran and molecular sieve (0.4 nm)at 0° C. The mixture was stirred at room temperature. After 1 h thereaction mixture was concentrated in vacuum, and the resulting solid waspurified by preparative thin layer chromatography (Merck, 20×20 cm,Silica gel 60 F₂₅₄, 1 mm) (CH₇Cl₂:MeOH, 100:1).

Synthesis Method E Amide Derivatives

A solution of (1.2 eq) acid chloride in dichloromethane was added to asolution of (1 eq) amine in dichloromethane and (1.2 eq) triethylamineat 0° C. The mixture was stirred at room temperature. After 1 h thereaction mixture was concentrated in vacuum, and the resulting solid waspurified by preparative thin layer chromatography (Merck, 20×20 cm,Silica gel 60 F₂₅₄, 1 mm) (n-hexane:EtOAc, 9:1).

Synthesis Method F Semicarbazide or Thiosemicarbazide Derivatives

A solution of (1.3 eq) isocyanate or (1.3 eq) isothiocyanate intetrahydrofuran was added to a solution of (1 eq) hydrazide intetrahydrofuran and molecular sieve (0.4 nm) at 0° C. The mixture wasstirred at room temperature. After 1 h the reaction mixture wasconcentrated in vacuum, and the resulting solid was purified bypreparative thin layer chromatography (Merck, 20×20 cm, Silica gel 60F₂₅₄, 1 mm) (CH₂Cl₂:MeOH, 100:5).

Synthesis Method G Hydrazide Derivatives

A solution of (1.2 eq) acid chloride in tetrahydrofuran was added to asolution of (1 eq) hydrazine in tetrahydrofuran and molecular sieve (0.4nm) at 0° C. The mixture was stirred at room temperature. After 1 h thereaction mixture was concentrated in vacuum, and the resulting solid waspurified by preparative thin layer chromatography (Merck, 20×20 cm,Silica gel 60 F₂₅₄, 1 mm) (CH₂Cl₂:MeOH, 100:1).

Synthesis Method H β-Ketoamides

The acyl Meldrum's acid (1.2 eq) was dissolved in anhydrous benzene(concentration approximately 0.4 mol/l), and the amine (1.0 eq) wasadded. In case of amine hydrochlorides, one equivalent of triethylamineor N,N-diisopropylethylamine was added. The mixture was refluxed untiltic showed complete conversion (typically, 4 to 6 h). The benzenesolutions were directly chromatographed on silica gel in an appropriatesolvent mixture (isohexane-ethyl acetate, dichloromethane-methanol, ordichloromethane-acetonitrile mixtures). Yields of the purified productstypically were in the range from 30 to 75%.

In the following Table 2, the synthesis method employed in each case forthe respective compound or whether the compound was obtained isindicated. Furthermore, the mass found by LC/(+)-ESI and LC/(−)-ESI massspectrometry, the molecular mass, the NMR data (300.13 MHz, residualsolvent peaks were used as internal standards (chloroform, δ7.26;methanol, δ3.31; dimethyl sulfoxide, δ2.49; abbreviations: ψ=pseudo,br.=broad, s=singulet, d=doublet, t=triplet, q=quartet, quint.=quintet,sext.=sextet, m_(c)=multiplet centered, m=multiplet, CH_(ar)=aromatic H,J=¹H-¹H coupling constant) and the IC₅₀ range as a measure ofanti-quorum sensing activity are indicated. The NMR data of the smallsignals due to enol-tautomers or possible rotamers of the3-oxo-carboxylic acid amides are not listed.

TABLE 2 Structure and biosensor assay results of the tested compounds.Synthesis method/ HPLC/MS # Compound supplier (ESI) ¹H-NMR (300 MHz)IC₅₀* 1

May-bridge — — +++ 2

E 313[M + H]⁺311[M − H]⁻ δ(CDCl₃) = 3.88 (s, 3H, OCH₃), 6.72 (d,J = 8.9Hz, 1H, H-3), 7.03 (d, J = 5.2Hz, 1H, H-4′), 7.46 (d, J = 5.3 Hz,1H,H-5′), 7.95 (dd, J = 8.9, 2.7 Hz,1H, H-4), 8.24 (d, J = 2.7 Hz, 1H,H-6), 8.65 (br.s, 1H, NH) +++ 3

May-bridge — — +++ 4

May-bridge — — + 5

D 282[M + H]⁺280[M − H]⁻ δ(CD₃OD) = 2.23 (s, 3H, CH₃), 3.79 (s,3H, 3H,OCH₃), 7.06-7.11 (m, 2H, H-4and H-2′), 7.50 (dd, J = 4.9, 1.1 Hz,1H,H-3), 7.69 (dd, J = 3.8, 1.1 Hz,1H, H-5), 9.71 (s, 1H, NH) + 6

May-bridge — — ++ 7

May-bridge — — +++ 8

E 276[M + H]⁺274[M − H]⁻ δ(CDCl₃) = 2.54 (s, 3H, SCH₃), 3.86 (s,3H,OCH₃), 6.70 (d, J = 8.9 Hz, 1H, H-3), 7.01 (t, J = 4.8 Hz, 1H,H-5′),7.85 (d, J = 6.3 Hz, 1H, H-4′), 7.97(d, J = 8.7 Hz, 1H, H-4),8.22-8.23(br.s, 2H, H-6 and NH), 8.46 (dd, J =4.8, 1.7 Hz, 1H, H-6′) + 9

E 308[M + H]⁺306[M − H]⁻ δ(CD₃OD) = 3.85 (s, 3H, OCH₃), 6.87 (d,J = 8.8Hz, 1H, H-3), 8.10 (dd, J =8.9, 2.6 Hz, 1H, H-4), 8.57 (d, J =2.5 Hz,1H, H-6), 8.64 (d, J = 2.1 Hz,1H, H-4′), 8.91 (d, J = 2.2 Hz, 1H, H-6′),9.13 (d, J = 1.9 Hz, 1H, H-2′),10.81 (s, 1H, NH) + 10

E 346[M + H]⁺344[M − H]⁻ δ(CDCl₃) = 7.63 (s, 2H, H-3′ and H-5′),7.83(dd, J = 8.8, 2.3 Hz, 1H, H-4),8.17 (d, J = 8.8 Hz, 1H, H-3), 8.28(d, J= 2.3 Hz, 1H, H-6), 8.63 (s, 1H,NH) + 11

E 248[M + H]⁺246[M − H]⁻ δ(CDCl₃) = 2.53 (s, 3H, CH₃), 7.24 (dd,J = 8.2,4.9 Hz, 1H, H-5), 7.82 (s,1H, H-3′), 7.87 (s, 1H, H-5′), 8.29(d, J = 4.4Hz, 1H, H-4), 8.36 (d, J =8.4 Hz, 1H, H-6), 9.09 (s, 1H, H-2),10.30(br.s, 1H, NH) +++ 12

D 312[M + H]⁺310[M − H]⁻ δ(CD₃OD) = 1.40 (t, J = 7.2 Hz, 3H,NCH₂CH₃),2.25 (s, 3H, CH₃), 3.82 (s,3H, NCH₃), 4.33 (q, J = 7.2 Hz, 2H,NCH₂CH₃),6.40 (br.s, 1H, CH_(ar)), 7.44(d, J = 1.8 Hz, 1H, CH_(ar)) +++ 13

D 262[M + H]⁺260[M − H]⁻ δ(CD₃OD) = 1.66 (s, 9H, N-tBu), 2.24(s, 3H,CH₃), 3.75 (s, 3H, NCH₃), 6.30(br.s, 1H, CH_(ar)), 6.50 (br.s, 1H,CH_(ar)),7.43 (d, J = 2.1 Hz, 1H, CH_(ar)) + 14

D 318[M + H]⁺316[M − H]⁻ δ(DMSO-d₆) = 3.73 (s, 3H, NCH₃), 6.72(s, 1H,H-4′), 7.25 (dd, J = 3.6, 5.1Hz, 1H, H-4), 7.43 (d, J = 8.3 Hz,2H,CH_(ar)), 7.80 (d, J = 8.7 Hz, 2H, CH_(ar)),7.90 (dd, J = 1.2, 4.8Hz, 1H, H-3),8.01 (dd, J = 0.9, 3.9 Hz, 1H, H-5),10.43 (s, 1H, NH) +++15

D 218[M + H]⁺216[M − H]⁻ δ(CD₃OD) = 3.65 (s, 3H, NCH₃), 6.44 (s,1H,H-4′), 6.92 (dd, J = 3.6, 5.1 Hz,1H, H-4″), 7.19-7.23 (m, 2H,CH_(ar)),7.38 (t, J = 8.1 Hz, 1H, CH_(ar)), 7.50(d, J = 8.1 Hz, 1H,CH_(ar)), 7.78 (d, J =7.8 Hz, 1H, CH_(ar)), 7.87 (d, J = 1.8 Hz,1H,CH_(ar)) +++ 16

D 384[M + H]⁺382[M − H]⁻ δ(DMSO-d₆) = 1.34 (m_(c), 2H, CH₂), 1.53(m_(c),2H, CH₂), 1.74 (m_(c), 2H, CH₂), 2.28(t, J = 7.2 Hz, 2H, CH₂), 3.45 (t,J =6.6 Hz, 2H, CH₂), 3.59 (s, 3H, NCH₃),6.55 (s, 1H, H-4), 7.33 (d, J =8.7Hz, 2H, CH_(ar)), 7.65 (d, J = 8.4 Hz, 2H,CH_(ar)), 9.86 (s, 1H, NH)+++ 17

D 286[M + H]⁺284[M − H]⁻ δ(CD₃OD) = 0.80 (t, J = 6.6 Hz, 3H,CH₃),1.21-1.34 (m, 6H, (CH₂)₃), 1.59(quint., J = 7.8 Hz, 2H, CH₂), 2.31 (t,J= 7.5 Hz, 2H, CH₂), 3.64 (s, 3H,NCH₃), 6.47 (s, 1H, H-4), 7.15-7.29(m,3H, CH_(ar)), 7.62 (d, J = 6.9 Hz, 2H,CH_(ar)) +++ 18

D 350[M + H]⁺ δ(DMSO-d₆) = 1.41 (m_(c), 2H, CH₂), 1.55(m_(c), 2H, CH₂),1.82 (m_(c), 2H, CH₂), 2.31(t, J = 6.9 Hz, 2H, CH₂), 3.51 (t, J =6.6 Hz,2H, CH₂), 3.70 (s, 3H, NCH₃),6.62 (s, 1H, H-4), 7.28 (t, J = 7.5Hz, 1H,CH_(ar)), 7.38 (t, J = 8.4 Hz, 2H,CH_(ar)), 7.74 (t, J = 6.9 Hz, 2H,CH_(ar)),9.95 (s, 1H, NH) +++ 19

D 292[M + H]⁺290[M − H]⁻ δ(CD₃OD) = 0.81 (t, J = 6.6 Hz, 3H,CH₃),1.22-1.33 (m, 6H, (CH₂)₃), 1.61(quint., J = 7.8 Hz, 2H, CH₂), 2.33 (t,J= 7.5 Hz, 2H, CH₂), 3.61 (s, 3H,NCH₃), 6.38 (s, 1H, H-4), 6.93 (t, J=4.5 Hz, 1H, H-4′), 7.20 (d, J = 4.5Hz, 2H, H-3′ and H-5′) +++ 20

D 356[M + H]⁺354[M − H]⁻ δ(CD₃OD) = 1.44 (m_(c), 2H, CH₂), 1.64(m_(c),2H, CH₂), 1.80 (m_(c), 2H, CH₂), 2.36 (t,J = 7.2 Hz, 2H, CH₂),3.37 (t, J = 6.6Hz, 2H, CH₂), 3.62 (s, 3H, NCH₃), 6.39(s, 1H, H-4), 6.93(t, J = 4.5 Hz, 1H,H-4′), 7.21 (d, J = 4.5 Hz, 2H, H-3′and H-5′) +++ 21

D 288[M + H]⁺286[M − H]⁻ δ(CD₃OD) = 0.92 (t, J = 7.2 Hz, 3H,CH₃), 1.38(m_(c), 6H, (CH₂)₃), 1.71(quint., J = 7.5 Hz, 2H, CH₂), 2.43 (t,J = 7.5Hz, 2H, CH₂), 3.68 (s, 3H,NCH₃), 7.45 (s, 1H, H-3) +++ 22

D 274[M + H]⁺ δ(CD₃OD) = 1.46 (m_(c), 2H, CH₂), 1.63 (m_(c),2H, CH₂),1.80 (m_(c), 2H, CH₂), 2.34 (t,J = 7.2 Hz, 2R, CH₂), 3.37 (t, J = 6.6Hz,2H, CH₂), 3.61 (s, 3H, NCH₃), 6.11(d, J = 2.1 Hz, 1H, H-4), 7.29 (d, J=2.1 Hz, 1H, H-3) +++ 23

D 352[M + H]⁺ δ(CD₃OD) = 1.50 (m_(c), 2H, CH₂), 1.66 (m_(c),2H, CH₂),1.79 (m_(c), 2H, CH₂), 2.37 (t,J = 7.2 Hz, 2H, CH₂), 3.37 (t, J = 6.6Hz,2H, CH₂), 3.60 (s, 3H, NCH₃), 7.36(s, 1H, H-3) +++ 24

D 210[M + H]⁺208[M − H]⁻ δ(CD₃OD) = 0.92 (t, J = 6.6 Hz, 3H,CH₃),1.34-1.46 (m, 6H, (CH₂)₃), 1.72(quint., J = 7.8 Hz, 2H, CH₂), 2.42 (t,J= 7.8 Hz, 2H, CH₂), 3.72 s, 3H,NCH₃), 6.22 (d, J = 2.1 Hz, 1H, H-4),7.39(d, J = 2.1 Hz, 1H, H-3) +++ 25

G 289[M + H]⁺287[M − H]⁻ δ(DMSO-d₆) = 7.33-7.37 (m, 2H, CH_(ar)),7.80(dd, J = 3.6, 5.4 Hz, 2H, CH_(ar)),8.87 (d, J = 4.8 Hz, 1H, CH_(ar)),9.89(s, 1H, NH), 10.71 (s, 1H, NH) +++ 26

G 301[M + H]⁺299[M − H]⁻ δ(DMSO-d₆) = 2.19 (s, 3H, CH₃), 3.95(s, 3H,NCH₃), 6.73 (s, 1H, H-4), 7.23(d, J = 4.8 Hz, 1H, CH_(ar)), 8.74 (d, J=4.8 Hz, 1H, CH_(ar)), 9.76 (s, 1H, NH),10.46 (s, 1H, NH) +++ 27

May-bridge — — +++ 28

May-bridge — — ++ 29

A 331[M + H]⁺329[M − H]⁻ δ(DMSO-d₆) = 7.21 (t, J = 4.5 Hz, 1H,H-4), 7.52(d, J = 8.7 Hz, 2H, CH_(ar)),7.85 (d, J = 4.8 Hz, 1H, H-3), 7.88(d, J =3.6 Hz, 1H, H-5), 8.03 (d, J =8.7 Hz, 2H, CH_(ar)), 10.57 (s, 1H,NH),10.62 (s, 1H, NH) + 30

May-bridge — — + 31

May-bridge — — ++ 32

May-bridge — — ++ 33

B 415[M + H]⁺413[M − H]⁻ δ(CD₃OD) = 7.15 (d, J = 5.3 Hz, 1H, H-4),7.53-7.55 (m, 2H, CH_(ar)), 7.61-7.63(m, 3H, CH_(ar)), 7.80 (d, J = 5.3Hz, 1H,H-5), 8.19 (s, 1H, H-3′) + 34

A 415[M + H]⁺413[M − H]⁻ δ(CD₃OD) = 7.05 (t, J = 5.1 Hz, 1H, H-4), 7.38(d, J = 9.0 Hz, 2H, CH_(ar)),7.47 (d, J = 9.0 Hz, 2H, CH_(ar)), 7.62(dd,J = 5.1, 1.2 Hz, 1H, H-3), 7.70(dd, J = 4.2, 1.5 Hz, 1H, H-5), 8.05(s,1H, H-3′) ++ 35

TimTec 237[M + H]⁺235[M − H]⁻ δ(DMSO-d₆) = 3.45 (dd, J = 1.8, 3.3 Hz,1H,CH_(ar)), 7.23 (dd, J = 3.6, 4.8 Hz,1H, CH_(ar)), 7.29 (d, J = 3.6 Hz,1H,CH_(ar)), 7.87-7.95 (m, 3H, CH_(ar)), 10.44(s, 1H, NH), 10.52 (s, 1H,NH) ++ 36

May-bridge — — ++ 37

May-bridge — — ++ 38

A 301[M + H]⁺299[M − H]⁻ δ(DMSO-d₆) = 3.89 (s, 3H, OCH₃), 6.67(dd, J =1.5, 3.3 Hz, 1H, H-4), 7.26(d, J = 3.6 Hz, 1H, H-3), 7.24 (d, J =3.3 Hz,1H, H-3), 7.91 (d, J = 1.5 Hz,1H, H-5), 7.94 (s, 1H, H-3′), 10.12(br.s,1H, NH), 10.36 (br.s, 1H, NH) +++ 39

A 315[M + H]⁺313[M − H]⁻ δ(DMSO-d₆) = 6.66 (dd, J = 1.8, 3.3 Hz,1H,H-4), 7.22 (d, J = 5.1 Hz, 1H, H-4′), 7.24 (d, J = 3.3 Hz, 1H, H-3),7.58(d, J = 5.1 Hz, 1H, H-5′), 7.90(d, J = 1.8 Hz, 1H, H-5), 10.37 (br.s,2H,NH) +++ 40

A 305[M + H]⁺303[M − H]⁻ δ(DMSO-d₆) = 6.59 (dd, J = 1.8, 3.3 Hz,1H,H-4), 7.17 (d, J = 3.6 Hz, 1H, H-3), 7.39 (s, 1H, H-4′), 7.83 (d, J =1.8Hz, 1H, H-5), 10.25 (s, 1H, NH),10.38 (s, 1H, NH) +++ 41

TimTec 321[M + H]⁺319[M − H]⁻ δ(DMSO-d₆) = 6.52 (dd, J = 1.8, 3.6 Hz,1H,H-4), 7.13 (dd, J = 1.8, 3.6 Hz,1H, H-3), 7.44-7.47 (m, 2H,CH_(ar)),7.76-7.79 (m, 2H, CH_(ar)), 7.99 (m_(c), 1H,H-5), 10.35 (s, 1H,NH), 10.42 (s, 1H,NH) +++ 42

May-bridge — — +++ 43

May-bridge — — +++ 44

B 331[M + H]⁺329[M − H]⁻ δ(CDCl₃) = 1.51 (t, J = 7.0 Hz, 3H,OCH₂CH₃),4.24 (q, J = 7.1 Hz, 2H,OCH₂CH₃), 6.80 (d, J = 5.4 Hz, 1H, H-4), 6.96(d, J = 5.3 Hz, 1H, H-4′),7.41 (d, J = 5.4 Hz, 1H, H-5), 7.46(d, J = 5.3Hz, 1H, H-5′), 9.97 (d, J =7.3 Hz, 1H, NH), 10.15 (d, J = 7.3Hz, 1H,NH) + 45

B 297[M + H]⁺295[M − H]⁻ δ(CDCl₃) = 1.50 (t, J = 7.0 Hz, 3H,OCH₂CH₃),4.25 (q, J = 7.0 Hz, 2H,OCH₂CH₃), 6.80 (d, J = 5.5 Hz, 1H, H-4), 7.01(dd, J = 6.0, 3.8 Hz, 1H, H-4′0), 7.40 (d, J = 5.4 Hz, 1H, H-5),7.43 (d,J = 3.9 Hz, 1H, H-3′), 7.62(d, J = 3.9 Hz, 1H, H-5′), 9.50 (br.s,1H,NH), 9.90 (d, J = 5.3 Hz, 1H, NH) +++ 46

AsInEx — — ++ 47

A 253[M + H]⁺251[M − H]⁻ δ(CD₃OD) = 7.06 (t, J = 3.9 Hz, 1H, H-4),7.41-7.48 (m, 2H, H-4′ and H-5′),7.63 (d, J = 4.8 Hz, 1H, H-3), 7.72(d,J = 4.8 Hz, 1H, H-5), 8.08 (s, 1H,H-2′) +++ 48

A 365[M + H]⁺363[M − H]⁻ δ(CDCl₃) = 6.87 (d, J = 4.1 Hz, 1H, H-2′), 7.03(d, J = 5.2 Hz, 1H, H-1),7.47 (d, J = 5.2 Hz, 1H, H-2), 7.49(d, J = 4.1Hz, 1H, H-1′) ++ 49

A 319[M + H]⁺ δ(CD₃OD) = 7.21 (d, J = 5.4 Hz, 2H, H-4and H-4′), 7.84 (d,J = 5.4 Hz, 2H, H-5 and H-5′) ++ 50

B 315[M + H]⁺ δ(CD₃OD) = 4.05 (s, 3H, OCH₃), 7.16(dd, J = 5.1, 3.9 Hz,1H, H-4′), 7.72(dd, J = 5.1, 1.2 Hz, 1H, H-3′), 7.81(dd, J = 3.9, 1.2Hz, 1H, H-5′), 7.96(s, 1H, H-5) ++ 51

SPECSand Bio-SPECS — — ++ 52

A 285[M − H]⁻ δ(DMSO-d₆) = 7.08 (d, J = 3.9 Hz, 1H,H-4′), 7.13 (d, J =4.2 Hz, 1H, H-4),7.68 (d, J = 3.9 Hz, 1H, H-3), 7.74(d, J = 3.9 Hz, 1H,H-3′), 7.78 (d, J =3.2 Hz, 1H, H-5′), 10.55 (s, 2H, NH) ++ 53

A 375[M + H]⁺373[M − H]⁻ δ(CD₃OD) = 2.44 (s, 3H, CH₃), 3.93 (s,3H,OCH₃), 6.75 (dd, J = 1.2, 3.9 Hz,1H, H-4), 7.52 (d, J = 3.6 Hz, 1H,H-3), 8.01 (s, 1H, H-5′) +++ 54

A 267[M + H]⁺265[M − H]⁻ δ(CD₃OD) = 2.52 (s, 3H, CH₃), 6.84 (d,J = 3.3Hz, 1H, H-4′), 7.16 (t, J =4.8 Hz, 1H, H-4), 7.61 (d, J = 3.6 Hz,1H,H-3′), 7.72 (d, J = 4.8 Hz, 1H, H-3), 7.80 (d, J = 4.2 Hz, 1H, H-5) +++55

A 331[M + H]⁺329[M − H]⁻ δ(CD₃OD) = 7.04-7.08 (m, 2H, H-4 and H-4′),7.58-7.65 (m, 2H, H-5 and H3′),7.70 (d, J = 3.6 Hz, 1H, H-5′) +++ 56

B 375[M + H]⁺373[M − H]⁻ δ(CD₃OD) = 1.41 (t, J = 6.9 Hz, 3H,CH₃), 4.27(q, J = 6.9 Hz, 2H, OCH₂),6.98 (d, J = 5.4 Hz, 1H, CH_(ar)), 7.07(d, J =5.4 Hz, 1H, CH_(ar)), 7.59 (d, J =5.7 Hz, 1H, CH_(ar)), 7.63 (d, J = 5.4Hz,1H, CH_(ar)) +++ 57

A 345[M + H]⁺343[M − H]⁻ δ(CD₃OD) = 2.64 (s, 3H, CH₃), 6.96 (dd,J = 0.9,3.6 Hz, 1H, CH_(ar)), 7.26 (d, J =5.1 Hz, 1H, CH_(ar)), 7.72 (d, J =3.6Hz, 1H, CH_(ar)), 7.82 (d, J = 5.1 Hz, 1H,CH_(ar)) +++ 58

A 319[M + H]⁺ δ(DMSO-d₆) = 7.10 (d, J = 5.1 Hz, 1H,H-4), 7.13 (d, J =4.2 Hz, 1H, H-4′),7.60 (d, J = 3.9 Hz, 1H, H-3′), 7.80(d, J = 5.1 Hz,1H, H-5) +++ 59

TimTec — — +++ 60

TimTec — — +++ 61

B 415[M + H]⁺413[M − H]⁻ δ(CD₃OD) = 7.01 (d, J = 5.4 Hz, 1H, H-4′),7.39-7.43 (m, 2H, CH_(ar)), 7.56 (d,J = 5.1 Hz, 1H, H-5′), 7.78-7.82(m,2H, CH_(ar)) ++ 62

B 413[M − H]⁻ δ(CDCl₃) = 7.03 (d, J = 3.7 Hz, 1H, H-4), 7.40 (d, J = 3.2Hz, 1H, H-3),7.45-7.48 (m, 2H, CH_(ar)), 7.77-7.87 (m,2H, CH_(ar)), 9.14(s, 1H, NH), 9.79 (s,1H, NH) ++ 63

B 350[M + H]⁺348[M − H]⁻ δ(CD₃OD) = 2.73 (s, 3H, CH₃), 4.05 (s,3H,NCH₃), 7.18 (dd, J = 5.1, 3.6 Hz,1H, H-4′), 7.75 (dd, J = 5.1, 1.2Hz,1H, H-3′), 7.83 (dd, J = 3.6, 1.2 Hz,1H, H-5′), 8.68 (s, 1H, H-6) +64

B 347[M − H]⁻ δ(CD₃OD) = 2.28 (s, 3H, CH₃), 4.08 (s,3H, NCH₃), 6.70 (s,1H, H-4), 7.57-7.62(m, 2H, CH_(ar)), 7.96-8.01 (m, 2H, CH_(ar)) + 65

May-bridge — — +++ 66

B 265[M + H]⁺263[M − H]⁻ δ(CD₃OD) = 2.25 (s, 3H, CH₃), 4.04 (s,3H,NCH₃), 6.65 (s, 1H, H-4), 7.17 (dd,J = 5.1, 3.9 Hz, 1H, H-4′), 7.73(dd,J = 5.1, 0.9 Hz, 1H, H-3′), 7.79 (d, J =3.9 Hz, 1H, H-5′) + 67

A 391[M + H]⁺389[M − H]⁻ δ(CDCl₃) = 1.33 (t, J = 7.1 Hz, 3H,NCH₂CH₃),1.83 (s, 3H, CH₃), 4.42 (dd,J = 14.3, 7.2 Hz, 2H, NCH₂CH₃), 6.85(d, J =4.1 Hz, 1H, H-4), 7.44 (d, J =4.1 Hz, 1H, H-3) + 68

A 305[M − H]⁻ δ(CD₃OD) = 1.68 (s, 9H, —C(CH₃)₃ ), 2.86(s, 3H, CH₃), 6.47(s, 1H, H-4′), 7.17(t, J = 3.9 Hz, 1H, H-4), 7.74 (dd, J =4.2, 0.9 Hz,1H, H-3), 7.82 (dd, J =3.6, 0.9 Hz, 1H, H-5) + 69

B 341[M + H]⁺339[M − H]⁻ δ(CDCl₃) = 1.22 (s, 9H, tBu), 4.00 (s,3H,NCH₃), 6.58 (s, 1H, H-4′), 6.81 (d,J = 3.9 Hz, 1H, H-4), 7.44 (d, J =3.9Hz, 1H, H-3) +++ 70

A 307[M + H]⁺305[M − H]⁻ δ(CD₃OD) = 1.33 (s, 9H, —C(CH₃)₃), 4.08(s, 3H,NCH₃), 6.80 (s, 1H, H-4′), 7.18(t, J = 3.6 Hz, 1H, H-4), 7.75 (dd, J=5.1, 1.2 Hz, 1H, H-3), 7.82 (d, J =3.6 Hz, 1H, H-5) + 71

A 435[M + H]⁺433[M − H]⁻ δ(CD₃OD) = 1.31 (t, J = 7.5 Hz, 3H,NCH₂CH₃),(s, 3H, CH₃), (q, J =7.2 Hz, 2H, NCH₂CH₃), 7.10 (d, J =4.2 Hz, 1H, H-4),7.48 (d, J = 3.9 Hz,1H, H-3) +++ 72

A 405[M + H]⁺403[M − H]⁻ δ(CD₃OD) = 1.29 (t, J = 6.9 Hz, 3H,NCH₂CH₃),2.12 (s, 3H, CH₃), 2.13 (s,3H, CH₃), 4.23 (q, J = 7.2 Hz, 2H,NCH₂CH₃),7.36 (s, 1H, H-5) + 73

A 391[M + H]⁺389[M − H]⁻ δ(CD₃OD) = 1.28 (t, J = 7.2 Hz, 3H,NCH₂CH₃),2.10 (s, 3H, CH₃), 4.20 (q, J =6.9 Hz, 2H, NCH₂CH₃), 6.94 (d, J =4.2 Hz,1H, H-4), 7.50 (d, J = 4.2 Hz,1H, H-3) +++ 74

A 513[M + H]⁺511[M − H]⁻ δ(DMSOd6) = 1.37 (t, J = 7.2 Hz, 3H,NCH₂CH₃),2.23 (s, 3H, CH₃), 4.28 (q, J =7.2 Hz, 2H, NCH₂CH₃), 7.94 (s, 1H, H-3),10.75 (s, 1H, NH), 11.09 (s, 1H,NH) + 75

TimTec 213[M + H]⁺211[M − H]⁻ δ(CD₃OD) = 0.90 (t, J = 7.5 Hz, 3H,CH₃),1.60 (sext., J = 7.5 Hz, 2H,CH₂), 2.18 (t, J = 7.2 Hz, 2H, CH₂),7.04(dd, J = 3.9, 5.1 Hz, 1H, H-4),7.60 (dd, J = 3.9, 5.1 Hz, 1H, H-3),7.65(dd, J = 3.9, 5.1 Hz, 1H, H-5) +++ 76

A 227[M + H]⁺225[M − H]⁻ δ(CD₃OD) = 1.01 (t, J = 7.5 Hz, 3H,CH₃), 1.71(sext., J = 7.5 Hz, 2H,CH₂), 2.28 (t, J = 7.5 Hz, 2H, CH₂),2.52 (s, 3H,CH₃), 6.82 (d, J = 3.9 Hz,1H, H-4), 7.57 (d, J = 3.6 Hz, 1H, H-3) ++ 77

A 291[M + H]⁺289[M − H]⁻ δ(CD₃OD) = 0.90 (t, J = 7.5 Hz, 3H,CH₃), 1.59(sext., J = 7.8 Hz, 2H,CH₂), 2.17 (t, J = 7.5 Hz, 2H, CH₂),7.05 (d, J =3.9 Hz, 1H, H-4), 7.43(d, J = 4.2 Hz, 1H, H-3) +++ 78

A 319[M + H]⁺ δ(DMSO-d₆) = 1.41 (m_(c), 2H, H-3′), 1.56(m_(c), 2H,H-2′), 1.81 (m_(c), 2H, H-4′),2.17 (t, J = 7.2 Hz, 2H, H-1′), 3.52(t, J= 6.6 Hz, 2H, H-5′), 7.16 (t, J =4.5 Hz, 1H, H-4), 7.81 (d, J = 4.2Hz,2H, H-3 and H-5), 9.82 (s, 1H,NH), 10.28 (s, 1H, NH) +++ 79

A 255[M + H]⁺253[M − H]⁻ δ(DMSO-d₆) = 0.86 (t, J = 6.9 Hz, 2H,H-6′),1.20-1.36 (m, 6H, H-3′, H-4′and H-5′), 1.53 (m_(c), 2H, H-2′), 2.17(t, J= 7.2 Hz, 2H, H-1′), 7.16 (t, J =4.5 Hz, 1H, H-4), 7.80-7.84 (m, 2H,H-3and H-5), 9.79 (s, 1H, NH), 10.27(s, 1H, NH) +++ 80

C 367[M + H]⁺365[M − H]⁻ δ(CDCl₃) = 1.45 (m_(c), 1H, H-3′), 1.68(m_(c),1H, H-2′), 1.80 (m_(c), 1H, H-4′),2.17 (s, 3H, CH₃), 2.35 (t, J = 7.4Hz,1H, H-1′), 3.33 (t, J = 6.7 Hz,1H, H-5′), 7.19 (s, 1H, H-5), 9.66 (d,J =6.4 Hz, 1H, NH), 9.82 (d, J = 6.3Hz, 1H, NH) +++ 81

C 303[M + H]⁺301[M − H]⁻ δ(CDCl₃) = 0.80 (t, J = 6.7 Hz, 1H, H-6′),1.18-1.28 (m, 3H, H-3′, H-4′ andH-5′), 1.62 (m_(c), 1H, H-2′), 2.16(s,3H, CH₃), 2.31 (t, J = 7.4 Hz, 1H, H-1′), 7.19 (s, 1H, H-5), 9.60 (d,J =6.5 Hz, 1H, NH), 9.84 (d, J = 6.4 Hz,1H, NH) +++ 82

A 333[M + H]⁺ δ(DMSO-d₆) = 1.41 (m_(c), 2H, CH₂), 1.53(m_(c), 2H, CH₂),1.79 (quint., J = 7.2Hz, 2H, CH₂), 2.16 (t, J = 7.2 Hz, 2H,CH₂), 2.46(s, 3H, CH₃), 3.52 (t, J =6.9 Hz, 2H, CH₂), 6.85 (dd, J = 0.9,4.8 Hz,1H, H-4), 7.61 (d, J = 3.9 Hz,1H, H-3), 9.77 (s, 1H, NH), 10.16 (s,1H,NH) +++ 83

A 269[M + H]⁺267[M − H]⁻ δ(DMSO-d₆) = 0.84 (t, J = 4.2 Hz, 3H,CH₃), 1.24(m_(c), 6H, (CH₂)₃), 1.48(quint., J = 7.2 Hz, 2H, CH₂), 2.18 (t,J = 7.5Hz, 2H, CH₂), 2.46 (s, 3H,CH₃), 6.85 (d, J = 3.9 Hz, 1H, H-4),7.60 (d, J= 3.3 Hz, 1H, H-3), 9.74(s, 1H, NH), 10.14 (s, 1H, NH) +++ 84

A 333[M + H]⁺331[M − H]⁻ δ(CD₃OD) = 0.82 (t, J = 6.9 Hz, 3H,CH₃),1.19-1.34 (m, 6H, (CH₂)₃), 1.56(quint., J = 7.2 Hz, 2H, CH₂), 2.19 (t,J= 7.5 Hz, 2H, CH₂), 7.05 (d, J = 4.2Hz, 1H, H-4), 7.43 (d, J = 4.2 Hz,1H,H-3) +++ 85

A 347[M + H]⁺345[M − H]⁻ δ(DMSO-d₆) = 0.89 (t, J = 6.9 Hz, 3H,CH₃),1.30-1.37 (m, 8H, (CH₂)₄), 1.57(quint., J = 6.6 Hz, 2H, CH₂), 2.19 (t,J= 7.5 Hz, 2H, CH₂), 7.24 (d, J = 5.1Hz, 1H, H-4), 7.87 (d, J = 5.1 Hz,1H,H-5), 9.95-10.16 (br.s, 2H, NH) +++ 86

A 325[M + H]⁺323[M − H]⁻ δ(CD₃OD) = 0.80 (t, J = 6.9 Hz, 3H,CH₃),1.14-1.32 (m, 16H, (CH₂)₈), 1.57(quint., J = 7.5 Hz, 2H, CH₂), 2.20 (t,J= 7.5 Hz, 2H, CH₂), 7.04 (dd, J =3.9, 4.8 Hz, 1H, H-4), 7.60 (dd, J=0.9, 4.8 Hz, 1H, H-3), 7.65 (dd, J =1.2, 4.2 Hz, 1H, H-5) +++ 87

A 281[M + H]⁺279[M − H]⁻ δ(DMSO-d₆) = 1.06 (m_(c), 2H, CH₂), 1.50(m_(c),6H, (CH₂)₃), 1.72 (m_(c), 3H, CH andCH₂), 2.16 (t, J = 7.8 Hz, 2H,CH₂),2.46 (s, 3H, CH₃), 6.65 (dd, J = 0.9,3.9 Hz, 1H, H-4), 7.61 (d, J =3.6 Hz,1H, H-3), 9.75 (s, 1H, NH), 10.14 (s,1H, NH) +++ 88

A 285[M + H]⁺283[M − H]⁻ δ(CD₃OD) = 1.96 (t, J = 7.2 Hz, 2H,CH₂), 2.36(t, J = 7.5 Hz, 2H, CH₂),2.44 (t, J = 7.5 Hz, 2H, CH₂), 2.51 (s,3H,CH₃), 3.67 (s, 3H, OCH₃), 6.82 (d,J = 3.9 Hz, 1H, H-4), 7.57 (d, J =3.6Hz, 1H, H-3) + 89

A 239[M + H]⁺237[M − H]⁻ δ(CD₃OD) = 1.11 (t, J = 6.6 Hz, 3H,CH₃),1.47-1.63 (m, 6H, (CH₂)₃), 1.86(quint., J = 7.2 Hz, 2H, CH₂), 2.48 (t,J= 7.5 Hz, 2H, CH₂), 6.79 (br.s, 1H,H-4), 7.39 (d, J = 3.6 Hz, 1H,H-3),7.88 (br.s, 1H, H-5) +++ 90

A 251[M + H]⁺249[M − H]⁻ δ(DMSO-d₆) = 1.14 (m_(c), 2H, CH₂), 1.60(m_(c),6H, (CH₂)₃), 1.80 (m_(c), 3H, CH andCH₂). 2.23 (t, J = 7.2 Hz, 2H,CH₂),6.70 (dd, J = 1.8, 3.6 Hz, 1H, H-4),7.62 (d, J = 3.6 Hz, 1H, H-3),7.94(d, J = 2.7 Hz, 1H, H-5), 9.82 (s, 1H,NH), 10.19 (s, 1H, NH) +++ 91

A 282[M + H]⁺280[M − H]⁻ δ(DMSO-d₆) = 0.75 (t, J = 6.9 Hz, 3H,CH₃),1.15-1.23 (m, 8H, (CH₂)₄), 1.43(quint., J = 6.9 Hz, 2H, CH₂), 2.05 (t,J= 7.8 Hz, 2H, CH₂), 2.17 (s, 3H,CH₃), 2.42 (s, 3H, CH₃), 9.71 (s,1H,NH), 9.76 (s, 1H, NH) +++ 92

A 373[M + H]⁺371[M − H]⁻ δ(DMSO-d₆) = 0.65 (t, J = 6.6 Hz, 3H,CH₃),0.97-1.12 (m, 11H, NCH₂CH₃ and(CH₂)₄), 1.33 (quint., J = 6.9 Hz,2H,CH₂), 1.92-1.97 (m, 5H, CH₃-3 and CH₂),3.98 (q, J = 7.5 Hz, 2H,NCH₂), 9.79(s, 1H, NH), 10.09 (s, 1H, NH) ++ 93

A 298[M + H]⁺296[M − H]⁻ δ(DMSO-d₆) = 0.81 (t, J = 7.2 Hz, 3H,CH₃),1.16-1.27 (m, 8H, (CH₂)₄), 1.48(m_(c), 2H, CH₂), 2.12 (t, J = 7.5 Hz,2H,CH₂), 7.71 (dd, J = 1.5, 5.1 Hz, 1H, H-5), 7.80 (br.s, 1H, H-3), 8.54(d, J =5.1 Hz, 1H, H-6), 9.94 (s, 1H, NH),10.62 (s, 1H, NH) +++ 94

A 298[M + H]⁺296[M − H]⁻ δ(DMSO-d₆) = 0.94 (t, J = 7.2 Hz, 3H,CH₃),1.34-1.39 (m, 8H, (CH₂)₄), 1.62(quint., J = 6.9 Hz, 2H, CH₂), 2.25 (t,J= 7.2 Hz, 2H, CH₂), 7.61 (dd, J =5.1, 7.8 Hz, 1H, H-5), 7.98 (dd, J=1.8, 7.5 Hz, 1H, H-4), 8.59 (dd, J =1.8, 4.5 Hz, 1H, H-6), 10.12 (s,1H,NH), 10.47 (s, 1H, NH) +++ 95

A 335[M + H]⁺333[M − H]⁻ δ(DMSO-d₆) = 0.96 (t, J = 7.2 Hz, 3H,CH₃), 3.09(s, 2H, CH₂), 3.86 (q, J =7.2 Hz, 2H, OCH₂), 6.97 (d, J = 5.4 Hz,1H,H-4), 7.60 (d, J = 5.1 Hz, 1H, H-5), 10.05 (s, 2H, NH) +++ 96

A 307[M + H]⁺305[M − H]⁻ δ(DMSO-d₆) = 1.33 (t, J = 7.2 Hz, 3H,CH₃), 3.49(s, 2H, CH₂), 4.24 (q, J =7.2 Hz, 2H, OCH₃), 7.55-7.64 (m, 2H,CH_(ar)),8.10 (d, J = 6.8 Hz, 1H, CH_(ar)),8.17 (d, J = 6.9 Hz, 1H, CH_(ar)),8.30(s, 1H, H-3), 10.39 (s, 1H, NH), 10.92(s, 1H, NH) ++ 97

A 323[M + H]⁺321[M − H]⁻ δ(CD₃OD) = 6.92 (d, J = 4.2 Hz, 1H,CH_(ar)),7.03 (d, J = 4.5 Hz, 1H, CH_(ar)),7.37 (d, J = 3.9 Hz, 1H, CH_(ar)),7.60(d, J = 4.5 Hz, 2H, CH_(ar)) +++ 98

A 283[M + H]⁺281[M − H]⁻ δ(CD₃OD) = 0.78 (t, J = 7.5 Hz, 3H,CH₃), 1.44(sext., J = 7.5 Hz, 2H,CH₂), 1.98 (t, J = 7.5 Hz, 2H, CH₂),6.96 (d, J =3.9 Hz, 1H, H-4), 7.37(d, J = 4.2 Hz, 1H, H-3) ++ 99

A 325[M + H]⁺323[M − H]⁻ δ(CD₃OD) = 0.80 (t, J = 6.9 Hz, 3H,CH₃),1.12-1.25 (m, 6H, (CH₂)₃), 1.40(quint., J = 7.2 Hz, 2H, CH₂), 2.02 (t,J= 7.5 Hz, 2H, CH₂), 6.96 (d, J = 4.2Hz, 1H, H-4), 7.37 (d, J = 4.2 Hz,1H,H-3) + 100

F 258[M + H]⁺256[M − H]⁻ δ(CD₃OD) = 0.82 (t, J = 7.5 Hz, 3H,CH₃), 1.25(sext, J = 7.5 Hz, 2H, CH₂),1.48 (quint., J = 7.5 Hz, 2H, CH₂),3.45 (t,J = 7.2 Hz, 2H, CH₂), 7.06(dd, J = 3.9, 3.9 Hz, 1H, H-4), 7.63(dd, J =1.2, 4.8 Hz, 1H, H-3), 7.69(d, J = 3.6 Hz, 1H, H-5) +++ 101

F 412[M + H]⁺410[M − H]⁻ δ(DMSO-d₆) = 1.04 (t, J = 7.2 Hz, 3H,CH₃),1.33-1.61 (m, 6H, CH₂), 3.17 (q,J = 6.3 Hz, 2H, CH₂), 6.71 (s, 1H, H-3),7.97 (s, 1H, NH), 8.08 (s, 1H,NH), 10.44 (s, 1H, NH) + 102

F 426[M + H]⁺424[M − H]⁻ δ(DMSO-d₆) = 7.32 (d, J = 3.9 Hz, 1H,H-4),7.49-7.59 (m, 2H, H-5′ and H-6′), 7.66 (d, J = 4.2 Hz, 1H, H-3),8.21 (s,1H, NH), 8.73 (s, 1H, NH),10.47 (s, 1H, NH) + 103

F 520[M + H]⁺518[M − H]⁻ δ(DMSO-d₆) = 7.65 (d, J = 8.7 Hz, 1H,CH_(ar)),7.85 (d, J = 8.7 Hz, 1H, CH_(ar)),7.89 (s, 1H, CH_(ar)), 8.13 (s, 1H,H-3),8.71 (s, 1H, NH), 9.43 (s, 1H, NH),10.61 (s, 1H, NH) ++ 104

F 486[M + H]⁺484[M − H]⁻ δ(DMSO-d₆) = 7.47 (d, J = 7.8 Hz, 1H,CH_(ar)),7.59 (t, J = 7.8 Hz, 1H, CH_(ar)),7.82 (d, J = 7.8 Hz, 1H, CH_(ar)),7.85(s, 1H, NH), 7.98-8.00 (br.s, 2H,CH_(arand NH), 8.01 (s, 1H, H-3), 10.58 (s,1H, NH)) +++ 105

F 356[M + H]⁺354[M − H]⁻ δ(DMSO-d₆) = 2.28 (s, 3H, CH₃), 2.52(s, 3H,SCH₃), 7.29 (d, J = 8.7 Hz, 2H,CH_(ar)), 7.52 (d, J = 8.7 Hz, 2H,CH_(ar)),7.69 (s, 1H, H-5), 8.37 (s, 1H, NH),8.94 (s, 1H, NH), 9.96 (s,1H, NH) +++ 106

F 388[M + H]⁺386[M − H]⁻ δ(DMSO-d₆) = 2.24 (s, 3H, CH₃), 7.48-7.53 (m,4H, CH_(ar)), 7.62 (s, 1H, H-5),8.54 (s, 1H, NH), 9.19 (s, 1H, NH),9.97(s, 1H, NH) +++ 107

F 388[M + H]⁺386[M − H]⁻ δ(DMSO-d₆) = 4.77 (s, 2H, CH₂), 7.08(t, J = 7.5Hz, 1H, CH_(ar)), 7.29 (d, J =7.5 Hz, 1H, CH_(ar)), 7.33 (d, J = 3.9Hz,1H, H-4), 7.42 (d, J = 7.5 Hz, 1H,CH_(ar)), 7.65-7.70 (m, 2H, H-3 andCH_(ar)),8.31 (s, 1H, NH), 8.61 (s, 1H, NH),10.48 (s, 1H, NH) +++ 108

F 344[M + H]⁺342[M − H]⁻ δ(DMSO-d₆) = 4.82 (s, 2H, CH₂), 7.13(t, J = 6.9Hz, 1H, CH_(ar)), 7.28 (d, J =4.2 Hz, 1H, H-4), 7.36 (d, J = 7.5 Hz,1H,CH_(ar)), 7.46 (d, J = 7.5 Hz, 1H,CH_(ar)), 7.71 (d, J = 8.4 Hz, 1H,CH_(ar)),7.79 (d, J = 3.9 Hz, 1H, H-3), 8.38(s, 1H, NH), 8.68 (s, 1H,NH), 10.55(s, 1H, NH) +++ 109

F 370[M + H]⁺368[M − H]⁻ δ(DMSO-d₆) = 3.55 (s, 3H, OCH₃), 6.69(d, J =7.5 Hz, 2H, CH_(ar)), 7.17-7.24(m, 3H, CH_(ar)), 7.53 (br.s, 1H,CH_(ar)),7.97 (s, 1H, NH), 8.53 (s, 1H, NH),10.19 (s, 1H, NH) + 110

F 376[M + H]⁺374[M − H]⁻ δ(DMSO-d₆) = 7.15-7.20 (m, 2H,CH_(ar)),7.33-7.41 (m, 2H, CH_(ar)), 7.69 (br.s,1H, CH_(ar)), 8.47 (s,1H, NH), 8.59 (s,1H, NH), 10.52 (s, 1H, NH) + 111

F 415[M + H]⁺413[M − H]⁻ δ(DMSO-d₆) = 7.71-7.75 (m, 4H, CH_(ar)),8.02(t, J = 4.2 Hz, 1H, CH_(ar)), 8.24(t, J = 5.1 Hz, 1H, CH_(ar)), 9.23(br.s,1H, NH), 9.97 (br.s, 1H, NH), 10.46(br.s, 1H, NH) + 112

F 360[M + H]⁺358[M − H]⁻ δ(DMSO-d₆) = 2.19 (s, 3H, CH₃), 6.88(t, J = 8.7Hz, 1H, CH_(ar)), 7.05-7.13(m, 2H, CH_(ar)), 7.49-7.54 (m, 2H,CH_(ar)),7.72 (d, J = 6.3 Hz, 1H, CH_(ar)), 7.82(d, J = 6.3 Hz, 1H,CH_(ar)),8.03 (d, J =6.9 Hz, 1H, CH_(ar)), 8.10 (s, 1H, NH),8.50 (s, 1H,NH), 10.26 (s, 1H, NH) + 113

H 238[M + H]⁺236[M − H]⁻ δ(CDCl₃) = 0.86 (ψ-t, J ≈ 7 Hz, 1H, 9-H),1.21-1.38 (m, 6H, 6-H, 7-H, 8-H),1.59 (ψ-quint, J = 7.3 Hz, 2H,5-H),2.63 (t, J = 7.4 Hz, 2H, 4-H), 3.60(s, 2H, 2H), 6.61 (s, br., 1H,ring-H), 7.46 (s, br., 1H, ring-H), 10.61(s, br., 1H, NH). + 114

H 252[M + H]⁺250[M − H]⁻ δ(CDCl₃) = 0.89 (ψ-t, J ≈ 7 Hz, 1H, 9-H),1.23-1.37 (m, 6H, 6-H, 7-H, 8-H),1.63 (ψ-quint, J = 7.3 Hz, 2H,5-H),2.58 (t, J = 7.3 Hz, 2H, 4-H), 3.66(s, 2H, 2-H), 3.87 (s, 2H,NCH₃), 6.44(d, J = 2.1 Hz, 1H, ring-H), 7.47 (d,J = 2.1 Hz, 1H, ring-H),9.85 (s, br.,1H, NH). + 115

H 294[M + H]⁺292[M − H]⁻ δ(CDCl₃) = 0.87 (ψ-t, J ≈ 7 Hz, 1H, 12-H),1.19-1.37 (m, 12H, 6-H, 7-H, 8-H,9-H, 10-H, 11-H), 1.61 (ψ-quint, J =7.3Hz, 2H, 5-H), 2.53 (t, J = 7.3 Hz,2H, 4-H), 3.57 (s, 2H, 2-H), 3.75(s,2H, NCH₃), 6.30 (d, J = 1.8 Hz, 1H,ring-H), 7.38 (d, J = 1.8 Hz,1H,ring-H), 9.55 (s, br., 1H, NH). + 116

H 266[M + H]⁺264[M − H]⁻ δ(CDCl₃) = 0.89 (ψ-t, J ≈ 7 Hz, 1H, 9-H),1.24-1.36 (m, 6H, 6-H, 7-H, 8-H),1.46 (t, J = 7.2 Hz, 3H, NCH₂CH₃),1.63(ψ-quint, J = 7.3 Hz, 2H, 5H), 2.58(t, J = 7.3 Hz, 2H, 4-H), 3.66(s, 2H,2-H), 4.21 (q, J = 7.3 Hz, 2H,NCH₂CH₃), 6.46 (d, J = 2.1 Hz,1H,ring-H), 7.49 (d, J = 2.1 Hz, 1H,ring-H), 9.85 (s, br., 1H, NH). +117

H 308[M + H]⁺306[M − H]⁻ δ(CDCl₃) = 0.88 (ψ-t, J ≈ 7 Hz, 1H, 12-H),1.22-1.37 (m, 12H, 6-H, 7-H, 8-H,9-H, 10-H, 11-H), 1.46 (t, J = 7.3Hz,3H, NCH₂CH₃), 1.64 (ψ-quint, J = 7.3Hz, 2H, 5-H), 2.58 (t, J = 7.3Hz, 2H,4-H), 3.61 (s, 2H, 2-H), 4.10 (q, J =7.3 Hz, 2H, NCH₂CH₃), 6.37(d, J = 1.8Hz, 1H, ring-H), 7.43 (d, J = 1.8 Hz,1H, ring-H), 9.56 (s,br., 1H, NH). + 118

H 266[M + H]⁺264[M − H]⁻ δ(CDCl₃) = 0.88 (ψ-t, J ≈ 7 Hz, 1H, 9-H),1.23-1.36 (m, 6H, 6-H, 7-H, 8-H),1.61 (ψ-quint, J = 7.3 Hz, 2H,5-H),2.22 (s, 3H, ring-CH₃), 2.57 (t, J =7.3 Hz, 2H, 4-H), 3.60 (s, 2H,2-H),3.72 (s, 3H, NCH₃), 6.15 (s, 1H, ring-H), 9.58 (s,br., 1H, NH). +119

H 308[M + H]⁺306[M − H]⁻ δ(CDCl₃) = 0.88 (ψ-t, J = 7 Hz, 1H, 12-H),1.21-1.36 (m, 12H, 6-H, 7-H, 8-H,9-H, 10-H, 11-H), 1.63 (ψ-quint, J =7.3Hz, 2H, 5-H), 2.22 (s, 3H, ring-CH₃), 2.57 (t, J = 7.3 Hz, 2H, 4-H),3.60(s, 2H, 2-H), 3.72 (s, 3H, NCH₃),6.14 (s, 1H, ring-H), 9.44 (s, br.,1H,NH). + 120

H 238[M + H]⁺236[M − H]⁻ δ(CDCl₃) = 0.88 (ψ-t, J ≈ 7 Hz, 1H, 9-H),1.17-1.34 (m, 6H, 6-H, 7-H, 8-H),1.59 (ψ-quint, J = 7.3 Hz, 2H,5-H),2.56 (t, J = 7.3 Hz, 2H, 4-H), 3.59(s, 2H, 2-H), 6.31 (ψ-t, J = 2.3Hz,1H, ring-H), 7.44 (dd, J = 2.3 Hz, J =0.6 Hz, 1H, ring-H), 7.49 (d, J= 2Hz, 1H, ring-H), 10.64 (s, br., 1H,NH). + 121

H 312[M + H]⁺310[M − H]⁻ δ(CDCl₃) = 0.88 (ψ-t, J ≈ 7 Hz, 1H, 9-H),1.21-1.36 (m, 6H, 6-H, 7-H, 8-H),1.65 (ψ-quint, J = 7.3 Hz, 2H,5-H),2.59 (t, J = 7.3 Hz, 2H, 4-H), 3.66(s, 2H, 2-H), 3.94 (s, 3H,CO₂CH₃),6.75 (dd, J = 5.8 Hz, J = 0.8 Hz, 1H,ring-H), 7.23 (d, J = 5.8Hz, 1H,ring-H), 11.88 (s, br., 1H, NH). + 122

H 354[M + H]⁺352[M − H]⁻ δ(CDCl₃) = 0.88 (ψ-t, J ≈ 7 Hz, 1H, 12-H),1.21-1.36 (m, 12H, 6-H, 7-H, 8-H,9-H, 10-H, 11-H), 1.65 (ψ-quint, J =7.3Hz, 2H, 5-H), 2.58 (t, J = 7.3 Hz,2H, 4-H), 3.66 (s, 2H, 2-H), 3.93(s,3H, CO₂CH₃), 6.74 (dd, J = 5.8 Hz, J =0.8 Hz, 1H, ring-H), 7.22 (d, J= 5.8Hz, 1H, ring-H), 11.88 (s, br., 1H,NH). + 123

H 340[M + H]⁺338[M − H]⁻ δ(CDCl₃) = 0.88 (ψ-t, J ≈ 7 Hz, 1H, 9-H),1.24-1.35 (m, 6H, 6-H, 7-H, 8-H),1.41 (t, J = 7.1 Hz, 3H,CO₂CH₂CH₃),1.63 (ψ-quint, J = 7.4 Hz, 2H, 5H),2.38 (d, J = 1.1 Hz, 3H,ring-CH₃),2.58 (t, J = 7.3 Hz, 2H, 4H), 3.63(s, 2H, 2H), 4.42 (q, J =7.1 Hz, 2H,CO₂CH₂CH₃), 6.39-6.41 (m, 1H, ring-H),11.97 (s, br., 1H,NH). + 124

H 382[M + H]⁺380[M − H]⁻ δ(CDCl₃) = 0.88 (ψ-t, J ≈ 7 Hz, 1H, 12-H),1.21-1.36 (m, 12H, 6-H, 7-H, 8-H,9-H, 10-H, 11-H), 1.41 (t, J = 7.1Hz,3H, CO₂CH₂CH₃), 1.63 (ψ-quint, J = 7.4Hz, 2H, 5-H), 2.38 (d, J = 1.1Hz, 3H,ring-CH₃), 2.58 (t, J = 7.3 Hz, 2H, 4-H), 3.63 (s, 2H, 2-H), 4.42(q, J =7.1 Hz, 2H, CO₂CH₂CH₃), 6.39-6.41 (m,1H, ring-H), 11.97 (s, br.,1H, NH). + 125

H 269[M + H]⁺267[M − H]⁻ δ(CDCl₃) = 0.88 (ψ-t, J ≈ 7 Hz, 1H, 9-H),1.23-1.37 (m, 6H, 6-H, 7-H, 8-H),1.61 (ψ-quint, J = 7.3 Hz, 2H,5-H),2.55 (s, 3H, ring-CH₃), 2.60 (t, J =7.3 Hz, 2H, 4-H), 3.84 (s, 2H,2-H),6.91 (s, 1H, ring-H). + 126

H 311[M + H]⁺309[M − H]⁻ δ(CDCl₃) = 0.88 (ψ-t, J ≈ 7 Hz, 1H, 12-H),1.22-1.37 (m, 12H, 6-H, 7-H, 8-H,9-H, 10-H, 11-H), 1.63 (ψ-quint, J =7.3Hz, 2H, 5-H), 2.42 (s, 3H, ring-CH₃), 2.58 (t, J = 7.3 Hz, 2H, 4-H),3.66(s, 2H, 2-H), 6.66 (s, 1H, ring-H), 10.51 (s, br., 1H, NH). + 127

H 255[M + H]⁺253[M − H]⁻ δ(CDCl₃) = 0.88 (ψ-t, J ≈ 7 Hz, 1H, 9-H),1.24-1.37 (m, 6H, 6-H, 7-H, 8-H),1.62 (ψ-quint, J = 7.3 Hz, 2H,5-H),2.59 (t, J = 7.3 Hz, 2H, 4-H), 3.71(s, 2H, 2-H), 7.00 (d, J = 3.7Hz, 1H,ring-H), 7.47 (d, J = 3.7 Hz, 1H,ring-H), [NH proton notvisible]. + 128

H 297[M + H]⁺295[M − H]⁻ δ(CDCl₃) = 0.88 (ψ-t, J ≈ 7 Hz, 1H, 12-H),1.21-1.37 (m, 12H, 6-H, 7-H, 8-H,9-H, 10-H, 11-H), 1.62 (ψ-quint, J =7.3Hz, 2H, 5-H), 2.61 (t, J = 7.3 Hz,2H, 4-H), 3.66 (s, 2H, 2-H), 7.00 (d,J= 3.6 Hz, 1H, ring-H), 7.49 (d, J =3.6 Hz, 1H, ring-H), 11.54 (s,br.,1H, NH). + 129

H 343[M + H]⁺341[M − H]⁻ δ(CDCl₃) = 0.85 (ψ-t, J = 7 Hz, 1H, 9-H),1.21-1.37 (m, 6H, 6-H, 7-H, 8-H),1.59 (ψ-quint, J = 7.3 Hz, 2H,5-H),2.38 (s, 3H, SCH₃), 2.56 (t, J = 7.3Hz, 2H, 4-H), 2.68 (s, 3H,COCH₃ ⁺),3.87 (s, br., 2H, 2-H), 10.88 (s, br.,1H, NH). + 130

H 239[M + H]⁺237[M − H]⁻ δ(CDCl₃) = 0.89 (ψ-t, J ≈ 7 Hz, 1H, 9-H),1.23-1.36 (m, 6H, 6-H, 7-H, 8-H),1.62 (ψ-quint, J = 7.3 Hz, 2H,5-H),2.57 (t, J = 7.3 Hz, 2H, 4-H), 3.60(s, 2H, 2-H), 7.01 (d, J = 1.7Hz, 1H,ring-H), 8.28 (dd, J = 1.7 Hz, J = 0.5Hz, 1H, ring-H), 9.90 (s,br., 1H,NH). + 131

H 281[M + H]⁺279[M − H]⁻ δ(CDCl₃) = 0.88 (ψ-t, J ≈ 7 Hz, 1H, 12-H),1.22-1.36 (m, 12H, 6-H, 7-H, 8-H,9-H, 10-H, 11-H), 1.62 (ψ-quint, J =7.3Hz, 2H, 5-H), 2.57 (t, J = 7.3 Hz,2H, 4-H), 3.60 (s, 2H, 2-H), 7.00 (d,J= 1.7 Hz, 1H, ring-H), 8.28 (dd, J =1.7 Hz, J = 0.5 Hz, 1H, ring-H),9.88(s, br., 1H, NH). + 132

H 253[M + H]⁺251[M − H]⁻ δ(CDCl₃) = 0.89 (ψ-t, J ≈ 7 Hz, 1H, 9-H),1.25-1.37 (m, 6H, 6-H, 7-H, 8-H),1.63 (ψ-quint, J = 7.3 Hz, 2H,5-H),2.27 (s, 3H, ring-CH₃), 2.56 (t, J =7.3 Hz, 2H, 4-H), 3.60 (s, 2H,2-H),6.20 (s, 1H, ring-H), 10.17 (s, br.,1H, NH). + 133

H 295[M + H]⁺293[M − H]⁻ δ(CDCl₃) = 0.88 (ψ-t, J ≈ 7 Hz, 1H, 12-H),1.20-1.37 (m, 12H, 6-H, 7-H, 8-H,9-H, 10-H, 11-H), 1.63 (ψ-quint, J =7.3Hz, 2H, 5-H), 2.26 (s, 3H, ring-CH₃), 2.56 (t, J = 7.3 Hz, 2H, 4H),3.60(s, 2H, 2-H), 6.20 (s, 1H, ring-H), 10.15 (s, br., 1H, NH). + 134

H 253[M + H]⁺251[M − H]⁻ δ(CDCl₃) = 0.88 (ψ-t, J ≈ 7 Hz, 1H, 9-H),1.25-1.38 (m, 6H, 6-H, 7-H, 8-H),1.61 (ψ-quint, J = 7.3 Hz, 2H,5-H),2.12 (d, J = 1.3 Hz, 1H, ring-CH₃),2.57 (t, J = 7.3 Hz, 2H, 4-H),3.68(s, br., 2H, 2-H), 7.12 (q, J = 1.3Hz, 1H, ring-H), [NH protonnotvisible]. + 135

H 278[M + H]⁺276[M − H]⁻ δ(CDCl₃) = 0.87 (ψ-t, J ≈ 7 Hz, 1H, 9-H),1.21-1.37 (m, 6H, 6-H, 7-H, 8-H),1.59 (ψ-quint, J = 7.3 Hz, 2H,5-H),2.41 (s, 3H, ring-CH₃), 2.57 (t, J =7.3 Hz, 2H, 4-H), 3.65 (s, 2H,2-H),10.10 (s, br., 1H, NH). ++ 136

H 291[M + H]⁺289[M − H]⁻ δ(CDCl₃) = 0.85 (ψ-t, J ≈ 7 Hz, 1H, 9-H),1.21-1.34 (m, 6H, 6-H, 7-H, 8-H),1.57 (ψ-quint, J = 7.3 Hz, 2H,5-H),1.97 (q, J = 0.8 Hz, 3H, ring-CH₃),2.13 (q, J = 0.9 Hz, 3H,ring-CH₃),2.55 (t, J = 7.4 Hz, 2H, 4-H), 3.60(s, 2H, 2-H), 9.81 (s, br.,1H, NH). + 137

H 333[M + H]⁺331[M − H]⁻ 0.88 (ψ-t, J ≈ 7 Hz, 1H, 12-H), 1.21-1.37 (m,12H, 6-H, 7-H, 8-H, 9-H, 10-H, 11-H), 1.62 (ψ-quint, J = 7.3 Hz,2H,5-H), 2.01 (q, J = 0.9 Hz, 3H,ring-CH₃), 2.17 (q, J = 0.9 Hz,3H,ring-CH₃), 2.57 (t, J = 7.4 Hz, 2H, 4-H), 3.60 (s, 2H, 2-H), 9.78 (s,br.,1H, NH). + 138

H 296[M + H]⁺294[M − H]⁻ δ(CDCl₃) = 0.84 (ψ-t, J ≈ 7 Hz, 1H, 9-H),1.17-1.35 (m, 6H, 6-H, 7-H, 8-H),1.57 (ψ-quint, J = 7.3 Hz, 2H,5-H),2.55 (t, J = 7.3 Hz, 2H, 4-H), 3.63(s, 2H, 2-H), 3.83 (s, 3H,CO₂CH₃),6.47 (d, J = 3.6 Hz, 1H, ring-H), 7.14(d, J = 3.6 Hz, 1H,ring-H), 10.15 (s,br., 1H, NH). + *+++: 1-50 μM; ++: 50-100 μM; +: >100μM; −not determined

2. Biosensor Assay

Quorum sensing inhibition of the compounds was investigated with the aidof the bioluminescent sensor strain Escherichia coli MT102 (pSB403)(Winson et al., FEMS Microbiol. Lett. 163:185-92, 1998). Plasmid pSB403contains the Photobacterium fischeri luxR gene together with the tuxIpromoter region as a transcriptional fusion to the bioluminescence genesluxCDABE of Photorhabdus luminescence. Although E. coli pSB403 exhibitsthe highest sensitivity for the Photobacterium fischeri quorum sensingsignal N-(3-oxohexanoyl)homoserine lactone (3-oxo-C6-HSL), a wide rangeof other HSL molecules are detected by the sensor (Winson et al., FEMSMicrobiol. Lett. 163:185-92, 1998; Geisenberger et al, FEMS Microbiol.Lett. 184:273-8, 2000).

Inhibitory studies were conducted in a microtitre dish assay as follows:the E. coli sensor strain grown over night in LB medium (Sambrook etal., Molecular Cloning: A Laboratory Maual. 2^(nd) Edn. Cold SpringHarbor Laboratory, New York, 1989) was diluted 1:4 and grown for another1 hour at 30° C. After addition of 3oxo-C6-HSL (final concentration 100nM) 100 μl of an exponential culture suspension were filled in the wellsof a FluoroNunc Polysorp microtitre dish. The test compounds were addedto the culture in different concentrations and bioluminescence wasmeasured after 4 hours of incubation at 30° C. with a Lamda Fluoro 320Plus reader (Bio-Tek Instruments). Inhibitor-mediated reduction of lightemission was correlated with the value obtained without addition of thetest compounds. IC₅₀ values (concentration of inhibitor required for 50%inhibition of the signal compared to the signal without inhibitor) weredetermined by using a fitting function after drawing a graph of theactivities of eight different inhibitor concentrations. The determinedIC₅₀ range of each compound is listed in Table 2.

To exclude the possibility that the inhibitory effect is attributed togrowth inhibition but not to a specific interaction of the test compoundwith the sensors quorum sensing system growth curves in the presence andabsence of the test compounds were compared. E. coli MT102 (pSB403) wasgrown in LB medium at 37° C. in the presence of 0.4 mM test compound.Growth was measured as optical density at 600 nm. None of the compoundslisted in Table 2 exhibit any growth inhibitory effects on the sensorstrain E. coli MT102 (pSB403). FIG. 2 shows the growth curves ofrepresentative compounds indicating a specific inhibitory effect of thecompounds on the quorum sensing system.

3. Inhibition of Protease Production

The inhibitory effect of the compounds on quorum sensing regulatedvirulence factors was demonstrated by investigating the expression ofextracellular proteases by Pseudomonas aeruginosa. The P. aeruginosamutant strain PAO-JP2 (Pearson et al., J. Bacteriol. 179:5756-67, 1997)carrying mutations in the quorum sensing genes lasI and rhlI is unableto produce extracellular proteolytic enzymes. Protease expression can becompletely restored by external addition of 3-oxo-C12-HSL. The proteaseassay was performed according to Riedel et at. (J. Bacteriol.183:1805-9, 2001) with few modifications. PAO-JP2 was grown in LB mediumat 30° C. and shaking at 250 rpm to an OD600 nm of 0.5. The testcompounds were added at a final concentration of 0.4 mM and the culturewas incubated for further 30 min at 30° C. and shaking at 250 rpm. Afteraddition of 3-oxo-C12-HSL at a final concentration of 0.3 μM thecultures were grown for an additional 6 hours at 30° C. and shaking at250 rpm. The proteolytic activity was measured as described by Ayora &Götz (Mol. Gen. Genet. 242:421-30, 1994). 50 μl culture supernatant wereincubated with Azocasein (250 μl 2%, Sigma, St. Louis, Mo.) for 1 hourat 37° C. After precipitation of undigested substrate withtrichloroacetic acid (1.2 ml 10%) for 20 minutes at room temperature,followed by 5 minutes centrifugation at 13000 rpm, NaOH (0.75 ml 1M) wasadded to the supernatant. The relative protease activity was measured asabsorbance at 440 nm (OD_(440nm)) of the supernatant divided by theoptical density of the culture (OD_(600nm)). FIG. 3 demonstrates theinhibitory effect of several compounds on protease production of P.aeruginosa PAO-JP2. The data presented are representative for at leastthree separate experiments.

To demonstrate that inhibition of protease production is due to aspecific interference with the quorum sensing system growth curves inthe presence and absence of the test compounds were compared. P.aeruginosa PAO-JP2 was grown in LB medium at 30° C. in the presence of0.4 mM test compound. Growth was measured as optical density at 600 nm.None of the compounds listed in Table 2 exhibit any growth inhibitoryeffects on P. aeruginosa PAO-JP2. FIG. 4 shows the growth curves ofrepresentative compounds indicating a specific inhibitory effect of thecompounds on the quorum sensing system.

4. Inhibition of Biofilm Formation

The bacterial biofilm formation assay was performed in polystyrenemicrotitre dishes (FluoroNunc Polysorp) according to the methoddescribed by O'Toole & Kolter (Mol. Microbiol. 28:449-61, 1998) andPratt & Kolter (Mol. Microbiol. 4 30; 285-93, 1998) with fewmodifications (Huber et al., Microbiology, 147:2517-28, 2001). Cellswere grown in the wells of the microtitre dishes in 100 μl AB medium(Clark & Maaloe, J. Mol. Biol. 23:99-112, 1967) supplemented with 10 mMsodium citrate (Sigma). After addition of the test compound (0.4 mM) thecells were incubated for 48 hours at 30° C. The medium was then removedand 100 μl of a 1% (w/v) aqueous solution of crystal violet (Merck) wasadded. Following staining at room temperature for 20 minutes, the dyewas removed and the wells were washed thoroughly with water. Forquantification of attached cells, the crystal violet was solubilized ina 80;20 (v/v) mixture of ethanol and acetone and the absorbance wasdetermined at 570 nm (Ultrospec Plus spectrometer, Pharmacia). FIGS. 5Aand 5B demonstrate the inhibitory effect of several compounds on biofilmformation of Burkholderia cepacia H11 (Römling et al., J. Infect. Dis.170:1616-21, 1994; Gotschlich et al., Syst. Appl. Microbiol. 24:1-14,2001). The data presented are representative for at least five separateexperiments.

To exclude the possibility that biofilm inhibition is attributed togrowth inhibition growth curves in the presence and absence of the testcompounds were compared. Burkholderia cepacia H111 was grown in LBmedium at 37° C. in the presence of 0.4 mM test compound. Growth wasmeasured as optical density at 600 nm. None of the compounds listed inTable 2 exhibit any growth inhibitory effects on the sensor strainBurkholderia cepacia H111. FIG. 6 shows the growth curves of the testedcompounds indicating a specific inhibitory effect of the compounds onthe quorum sensing system.

1-26. (canceled)
 27. A compound of Formula (XIII)

or a pharmaceutically acceptable salt or physiologically functionalderivative thereof, wherein A⁶ is pyrazolyl, which may be optionallysubstituted with one or more R³; m is 1; R¹² is H, CH₃, CH₂CH₃, OCH₃,OCH₂CH₃, OH, or SH; r is 1; A⁷ is C(O) or C(S); A⁸ is C(R¹⁴)₂; each R¹⁴independently is H, alkyl, alkoxy, OH, or SH; A⁹ is C(O) or C(S); q is 0or 1; A⁵ is alkyl or heteroaryl, each of which may be optionallysubstituted with one or more R³; each R³ independently is OR⁴, SR⁴,hydroxyalkyl, hydroxyalkylamino, cycloalkyl, halogen, haloalkyl,haloalkoxy, NO₂, CN, SO₂NR⁴R⁵, CO₂NR⁴R⁵, COR⁴, CO₂R⁴, SO₂R⁴, SO₃R⁴,NR⁴R⁵, alkyl, aryl, aryl substituted with halogen, or heteroaryl; eachR⁴ independently is H, alkyl, cycloalkyl, aryl, or heteroaryl; and eachR⁵ independently is H, O-alkyl, O-aryl, alkyl, heteroaryl, or aryl. 28.The compound of claim 27 wherein A⁵ is C₆-C₈ alkyl.
 29. The compound ofclaim 27 wherein A⁹ is C(O).
 30. The compound of claim 27 wherein A⁸ isCH₂.
 31. The compound of claim 27 wherein A⁷ is C(O).
 32. The compoundof claim 27 wherein R¹² is H.
 33. The compound of claim 27 wherein A⁶ is

wherein a is 0, 1, or
 2. 34. The compound of claim 27 wherein A¹ is


35. A compound selected from:

or a pharmaceutically acceptable salt or physiologically acceptablederivative thereof.
 36. A method for inhibiting the production of avirulence factor comprising contact with a compound of claim
 27. 37. Amethod for inhibiting the production of a virulence factor comprisingcontact with a compound of claim
 35. 38. The method of claim 36 for thetreatment or prevention of bacterial damage or disease.
 39. The methodof claim 37 for the treatment or prevention of bacterial damage ordisease.
 40. The method of claim 38 wherein the bacteria is Pseudomonasaeruginosa or Burkholderia cepacia.
 41. The method of claim 39 whereinthe bacteria is Pseudomonas aeruginosa or Burkholderia cepacia.
 42. Acomposition for inhibiting biofilm formation comprising a compound ofclaim
 27. 43. A composition for inhibiting biofilm formation comprisinga compound of claim 35.